bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2023–04–16
forty-nine papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death.
  2. Validation and refinement of the 2022 European LeukemiaNet genetic risk stratification of acute myeloid leukemia.
  3. Impact of disease burden on clinical outcomes of AML patients receiving allogeneic hematopoietic cell transplantation: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.
  4. Impact of KRAS and NRAS mutations on outcomes in acute myeloid leukemia.
  5. Activity of luspatercept and ESAs combination for treatment of anemia in lower-risk myelodysplastic syndromes.
  6. Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1.
  7. Matched related versus unrelated versus haploidentical donors for allogeneic transplantation in AML patients achieving first complete remission after two induction courses: a study from the ALWP/EBMT.
  8. Venetoclax for Acute Myeloid Leukemia in Pediatric Patients: A Texas Medical Center Experience.
  9. Phase 1/1b study of azacitidine and hedgehog pathway inhibitor sonidegib in patients with myeloid neoplasms.
  10. Higher-dose venetoclax with measurable residual disease-guided azacitidine discontinuation in newly diagnosed acute myeloid leukemia.
  11. Dual inhibition of EZH2 and G9A/GLP histone methyltransferases by HKMTI-1-005 promotes differentiation of acute myeloid leukemia cells.
  12. MOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins.
  13. Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.
  14. TP53 mutation variant allele frequency of ≥10% is associated with poor prognosis in therapy-related myeloid neoplasms.
  15. Statin Use in Myelodysplastic Syndromes Is Associated with a Better Survival and Decreased Progression to Leukemia.
  16. Therapeutic Targets in Myelodysplastic Neoplasms: Beyond Hypomethylating Agents.
  17. Inflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis.
  18. Posttransplant MRD and T-cell chimerism status predict outcomes in patients allografted with AML/MDS.
  19. IPSS-M in myelodysplastic neoplasms arising from aplastic anemia and paroxysmal nocturnal hemoglobinuria.
  20. M2 macrophages drive leukemic transformation by imposing resistance to phagocytosis and improving mitochondrial metabolism.
  21. Interrogating bromodomain inhibitor resistance in KMT2A-rearranged leukemia through combinatorial CRISPR screens.
  22. Alemtuzumab and CXCL9 levels predict likelihood of sustained engraftment after reduced intensity conditioning HCT.
  23. Quantification of measurable residual disease using duplex sequencing in adults with acute myeloid leukemia.
  24. Outcomes of Older Adults With AML Treated in Community Versus Academic Centers: An Analysis of Alliance Trials.
  25. Transcriptional and genomic characterization of measurable residual disease in acute myeloid leukaemia.
  26. CD33 BiTE® molecule-mediated immune synapse formation and subsequent T-cell activation is determined by the expression profile of activating and inhibitory checkpoint molecules on AML cells.
  27. Clonal Hematopoiesis in Older Patients with Breast Cancer Receiving Chemotherapy.
  28. Therapeutic targeting of ACLY in T-ALL in vivo.
  29. Stein EM. IDH2 inhibition in AML. Blood. 2023;141(2):124-125.
  30. Emerging drugs targeting cellular redox homeostasis to eliminate acute myeloid leukemia stem cells.
  31. Clinical Impact of Minimal Residual Disease in Blood and Bone Marrow of Children with Acute Myeloid Leukemia.
  32. Restoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response.
  33. Outcome of patients with newly diagnosed AML admitted to the ICU, including preemptive admission - a multi-center study.
  34. The Role of Inflammation in the Initiation and Progression of Myeloid Neoplasms.
  35. Momelotinib Long-Term Safety and Survival in Myelofibrosis: Integrated Analysis of Phase 3 Randomized-Controlled Trials.
  36. Oncogenic drivers dictate immune control of acute myeloid leukemia.
  37. Real-world outcomes of frontline venetoclax-based therapy in older adults with acute myeloid leukemia: an analysis utilizing EHR data.
  38. Multi-omics of Bohring-Opitz syndrome truncating ASXL1 mutations identify canonical and non-canonical Wnt signaling dysregulation.
  39. High Throughput Fluorescence-Based In Vitro Experimental Platform for the Identification of Effective Therapies to Overcome Tumour Microenvironment-Mediated Drug Resistance in AML.
  40. New insights into the clinical characteristics of SETD2-mutated acute myeloid leukaemia.
  41. Gold is gold even in mud: NPM1 mutations in T-AML.
  42. Elevated enhancer-oncogene contacts and higher oncogene expression levels by recurrent CTCF inactivating mutations in acute T cell leukemia.
  43. Observation and treatment in DDX41-mutated acute myeloid leukemia and myelodysplastic syndrome.
  44. Clonal haematopoiesis and risk of chronic liver disease.
  45. Associations of minor histocompatibility antigens with outcomes following allogeneic hematopoietic cell transplantation.
  46. PI3K Inhibition Restores and Amplifies Response to Ruxolitinib in patients with Myelofibrosis.
  47. Venetoclax plus hypomethylating agents versus intensive chemotherapy for hematological relapse of myeloid malignancies after allo-HSCT.
  48. Phase II Study of Myeloablative 8/8- or 7/8-Matched Allotransplantation with Post-Transplant Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil: Marked Reduction in GVHD Risk Without Increased Relapse Risk Compared to Historical Cyclosporine/Methotrexate.
  49. Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease.
  1. Nat Commun. 2023 Apr 14. 14(1): 2132
    Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death.
    Keith Woodley, Laura S Dillingh, George Giotopoulos, Pedro Madrigal, Kevin M Rattigan, Céline Philippe, Vilma Dembitz, Aoife M S Magee, Ryan Asby, Louie N van de Lagemaat, Christopher Mapperley, Sophie C James, Jochen H M Prehn, Konstantinos Tzelepis, Kevin Rouault-Pierre, George S Vassiliou, Kamil R Kranc, G Vignir Helgason, Brian J P Huntly, Paolo Gallipoli.
      Resistance to standard and novel therapies remains the main obstacle to cure in acute myeloid leukaemia (AML) and is often driven by metabolic adaptations which are therapeutically actionable. Here we identify inhibition of mannose-6-phosphate isomerase (MPI), the first enzyme in the mannose metabolism pathway, as a sensitizer to both cytarabine and FLT3 inhibitors across multiple AML models. Mechanistically, we identify a connection between mannose metabolism and fatty acid metabolism, that is mediated via preferential activation of the ATF6 arm of the unfolded protein response (UPR). This in turn leads to cellular accumulation of polyunsaturated fatty acids, lipid peroxidation and ferroptotic cell death in AML cells. Our findings provide further support to the role of rewired metabolism in AML therapy resistance, unveil a connection between two apparently independent metabolic pathways and support further efforts to achieve eradication of therapy-resistant AML cells by sensitizing them to ferroptotic cell death.
    DOI:  https://doi.org/10.1038/s41467-023-37652-0
  2. Leukemia. 2023 Apr 11.
    Validation and refinement of the 2022 European LeukemiaNet genetic risk stratification of acute myeloid leukemia.
    Christian Rausch, Maja Rothenberg-Thurley, Annika Dufour, Stephanie Schneider, Hanna Gittinger, Cristina Sauerland, Dennis Görlich, Utz Krug, Wolfgang E Berdel, Bernhard J Woermann, Wolfgang Hiddemann, Jan Braess, Michael von Bergwelt-Baildon, Karsten Spiekermann, Tobias Herold, Klaus H Metzeler.
      The revised 2022 European LeukemiaNet (ELN) AML risk stratification system requires validation in large, homogeneously treated cohorts. We studied 1118 newly diagnosed AML patients (median age, 58 years; range, 18-86 years) who received cytarabine-based induction chemotherapy between 1999 and 2012 and compared ELN-2022 to the previous ELN-2017 risk classification. Key findings were validated in a cohort of 1160 mostly younger patients. ELN-2022 reclassified 15% of patients, 3% into more favorable, and 12% into more adverse risk groups. This was mainly driven by patients reclassified from intermediate- to adverse-risk based on additional myelodysplasia-related mutations being included as adverse-risk markers. These patients (n = 79) had significantly better outcomes than patients with other adverse-risk genotypes (5-year OS, 26% vs. 12%) and resembled the remaining intermediate-risk group. Overall, time-dependent ROC curves and Harrel's C-index controlling for age, sex, and AML type (de novo vs. sAML/tAML) show slightly worse prognostic discrimination of ELN-2022 compared to ELN-2017 for OS. Further refinement of ELN-2022 without including additional genetic markers is possible, in particular by recognizing TP53-mutated patients with complex karyotypes as "very adverse". In summary, the ELN-2022 risk classification identifies a larger group of adverse-risk patients at the cost of slightly reduced prognostic accuracy compared to ELN-2017.
    DOI:  https://doi.org/10.1038/s41375-023-01884-2
  3. Bone Marrow Transplant. 2023 Apr 11.
    Impact of disease burden on clinical outcomes of AML patients receiving allogeneic hematopoietic cell transplantation: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.
    Iman Abou Dalle, Myriam Labopin, Nicolaus Kröger, Thomas Schroeder, Jürgen Finke, Matthias Stelljes, Andreas Neubauer, Didier Blaise, Ibrahim Yakoub-Agha, Urpu Salmenniemi, Edouard Forcade, Maija Itäla-Remes, Peter Dreger, Gesine Bug, Jakob Passweg, Michael Heuser, Goda Choi, Eolia Brissot, Sebastian Giebel, Arnon Nagler, Fabio Ciceri, Ali Bazarbachi, Mohamad Mohty.
      Pre-transplant detectable measurable residual disease (MRD) is still associated with high risk of relapse and poor outcomes in acute myeloid leukemia (AML). We aimed at evaluating the impact of disease burden on prediction of relapse and survival in patients receiving allogeneic hematopoietic cell transplantation (allo-HCT) in first remission (CR1). We identified a total of 3202 adult AML patients, of these 1776 patients were in CR1 and MRD positive and 1426 patients were primary refractory at time of transplant. After a median follow-up of 24.4 months, non-relapse mortality and relapse rate were significantly higher in the primary refractory group compared to the CR1 MRD positive group (Hazards Ratio (HR) = 1.82 (95% CI: 1.47-2.24) p < 0.001 and HR = 1.54 (95% CI: 1.34-1.77), p < 0.001), respectively. Leukemia-free survival (LFS) and overall survival (OS) were significantly worse in the primary refractory group (HR = 1.61 (95% CI: 1.44-1.81), p < 0.001 and HR = 1.71 (95% CI: 1.51-1.94), p < 0.001, respectively). Our real-life data suggest that patients in CR1 and MRD positive at time of transplant could still be salvaged by allo-HCT with a 2-year OS of 63%, if negative MRD cannot be obtained and their outcomes are significantly better than patients transplanted with active disease.
    DOI:  https://doi.org/10.1038/s41409-023-01961-1
  4. Leuk Lymphoma. 2023 Apr 12. 1-10
    Impact of KRAS and NRAS mutations on outcomes in acute myeloid leukemia.
    Moaath K Mustafa Ali, Matthew T Williams, Elizabeth M Corley, Fahad AlKaabba, Sandrine Niyongere.
      The prognostic significance of RAS mutations in AML is poorly understood. In this ambispective cohort study of 239 newly-diagnosed AML patients at the University of Maryland, we assessed the median overall survival (mOS) and median event-free survival (mEFS) in RAS wild-type (WT) AML (n = 196), KRAS-mutated AML (n = 11), NRAS-mutated AML (n = 25), and KRAS/NRAS-mutated AML (n = 7). We used propensity score to adjust outcomes. NRAS-mutated AML had a similar response rate to first-line treatment and mOS compared to RAS-WT AML (57 vs. 54%, p = 0.8, 22.7 vs. 14.6 months, p = 0.7). The mOS of KRAS-mutated AML was shorter compared to RAS-WT AML (p = 0.049) and NRAS-mutated AML (p = 0.02). KRAS-mutated AML treated with anthracycline-based first-line regimens had a lower relative mortality compared to treatment with hypomethylating agents with venetoclax (HR <0.01, p = 0.04) and without venetoclax (HR <0.01, p = 0.04). This study demonstrates that KRAS but not NRAS mutations are associated with worse outcomes in AML.NOVELTY STATEMENTWhat is the new aspect of your work? The clinical significance of RAS mutations remains poorly defined and prior studies have yielded conflicting results. We used causal inferential methods, propensity score modeling, to determine the impact of KRAS and NRAS mutation on survival in newly diagnosed AML patients, independent of other risk factors. Moreover, we analyzed the outcomes of KRAS and NRAS-mutated AML patients receiving first-line therapy with hypomethylating agents and other non-anthracycline-based regimens. We provided a detailed description of RAS-mutated AML, including co-occurring mutations and cytogenetic abnormalities.What is the central finding of your work? KRAS mutations but not NRAS mutations in AML are directly linked to worse outcomes even after controlling for differences in AML type, co-occurring cytogenetic changes, treatment regimens, and comorbidities. KRAS-mutated AML has a higher relative mortality when treated with a hypomethylating agent-based first-line induction regimen compared to treatment with an anthracycline-based regimen.What is (or could be) the specific clinical relevance of your work? Our findings can help refine our genetic profiles of AML, improve prognostic models, and better stratify treatment regimens.
    Keywords:  Acute myeloid leukemia; KRAS; NRAS; RAS; event-free survival; myeloid mutations; outcomes; overall survival; prognosis
    DOI:  https://doi.org/10.1080/10428194.2023.2190432
  5. Blood Adv. 2023 Apr 14. pii: bloodadvances.2023009781. [Epub ahead of print]
    Activity of luspatercept and ESAs combination for treatment of anemia in lower-risk myelodysplastic syndromes.
    Rami S Komrokji, Luis E Aguirre, Najla Al-Ali, Onyee Chan, Zhuoer Xie, Andrew T Kuykendall, Kendra L Sweet, Jeffrey E Lancet, Eric Padron, David A Sallman.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2023009781
  6. Blood Cancer J. 2023 Apr 13. 13(1): 53
    Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1.
    Warren Fiskus, Christopher P Mill, Christine Birdwell, John A Davis, Kaberi Das, Steffen Boettcher, Tapan M Kadia, Courtney D DiNardo, Koichi Takahashi, Sanam Loghavi, Michael J Soth, Tim Heffernan, Gerard M McGeehan, Xinjia Ruan, Xiaoping Su, Christopher R Vakoc, Naval Daver, Kapil N Bhalla.
      Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse. Utilizing single-cell RNA-Seq, ChiP-Seq, ATAC-Seq, RNA-Seq, RPPA, and mass cytometry (CyTOF) analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy in AML cells harboring MLL1-r or mtNPM1. Notably, MI-mediated genome-wide, concordant, log2 fold-perturbations in ATAC-Seq and RNA-Seq peaks were observed at the loci of MLL-FP target genes, with upregulation of mRNAs associated with AML differentiation. MI treatment also reduced the number of AML cells expressing the stem/progenitor cell signature. A protein domain-focused CRISPR-Cas9 screen in MLL1-r AML cells identified targetable co-dependencies with MI treatment, including BRD4, EP300, MOZ and KDM1A. Consistent with this, in vitro co-treatment with MI and BET, MOZ, LSD1 or CBP/p300 inhibitor induced synergistic loss of viability of AML cells with MLL1-r or mtNPM1. Co-treatment with MI and BET or CBP/p300 inhibitor also exerted significantly superior in vivo efficacy in xenograft models of AML with MLL1-r. These findings highlight novel, MI-based combinations that could prevent escape of AML stem/progenitor cells following MI monotherapy, which is responsible for therapy-refractory AML relapse.
    DOI:  https://doi.org/10.1038/s41408-023-00826-6
  7. Bone Marrow Transplant. 2023 Apr 12.
    Matched related versus unrelated versus haploidentical donors for allogeneic transplantation in AML patients achieving first complete remission after two induction courses: a study from the ALWP/EBMT.
    Arnon Nagler, Myriam Labopin, Stephan Mielke, Jakob Passweg, Didier Blaise, Tobias Gedde-Dahl, Jan J Cornelissen, Urpu Salmenniemi, Ibrahim Yakoub-Agha, Péter Reményi, Gerard Socié, Gwendolyn van Gorkom, Hélène Labussière-Wallet, Xiao-Jun Huang, Marie Thérèse Rubio, Jenny Byrne, Charles Craddock, Laimonas Griškevičius, Fabio Ciceri, Mohamad Mohty.
      We compared transplants (HSCT) from matched related siblings (MSD) with those from matched 10/10 and mismatched 9/10 unrelated (UD) and T-replete haploidentical (Haplo) donors in acute myeloid leukemia (AML) in first complete remission (CR1) achieved after two inductions, a known poor prognostic factor. One thousand two hundred and ninety-five patients were included: MSD (n = 428), UD 10/10 (n = 554), UD 9/10 (n = 135), and Haplo (n = 178). Acute GVHD II-IV was higher in all groups compared to MSD. Extensive chronic (c) GVHD was significantly higher in UD 9/10 (HR = 2.52; 95% CI 1.55-4.11, p = 0.0002) and UD 10/10 (HR = 1.48; 95% CI 1.03-2.13, p = 0.036) and cGVHD all grades were higher in UD 9/10 vs MSD (HR = 1.77; 95% CI 1.26-2.49, p = 0.0009). Non-relapse mortality was higher in all groups compared to MSD. Relapse incidence, leukemia-free, and overall survival did not differ significantly between donor types. Finally, GVHD-free relapse-free survival was lower in HSCT from UD 9/10 (HR = 1.56, 95% CI 1.20-2.03, p = 0.0009) but not in those from UD 10/10 (HR = 1.13, p = 0.22) and Haplo donors (HR = 1.12, p = 0.43) compared to MSD. In conclusion, in AML patients undergoing HSCT in CR1 achieved after two induction courses 10/10 UD and Haplo but not 9/10 UD donors are comparable alternatives to MSD.
    DOI:  https://doi.org/10.1038/s41409-023-01980-y
  8. Cancers (Basel). 2023 Mar 26. pii: 1983. [Epub ahead of print]15(7):
    Venetoclax for Acute Myeloid Leukemia in Pediatric Patients: A Texas Medical Center Experience.
    Adriana Trabal, Amber Gibson, Jiasen He, David McCall, Michael Roth, Cesar Nuñez, Miriam Garcia, Meredith Buzbee, Laurie Toepfer, Aram Bidikian, Naval Daver, Tapan Kadia, Nicholas J Short, Ghayas C Issa, Farhad Ravandi, Courtney D DiNardo, Guillermo Montalban Bravo, Sofia Garces, Andrea Marcogliese, Hana Paek, Zoann Dreyer, Julienne Brackett, Michele Redell, Joanna Yi, Guillermo Garcia-Manero, Marina Konopleva, Alexandra Stevens, Branko Cuglievan.
      The BCL-2 inhibitor venetoclax improves survival for adult patients with acute myeloid leukemia (AML) in combination with lower-intensity therapies, but its benefit in pediatric patients with AML remains unclear. We retrospectively reviewed two Texas Medical Center institutions' experience with venetoclax in 43 pediatric patients with AML; median age 17 years (range, 0.6-21). This population was highly refractory; 44% of patients (n = 19) had ≥3 prior lines of therapy, 37% (n = 16) had received a prior bone marrow transplant, and 81% (n = 35) had unfavorable genetics KMT2A (n = 17), WT1 (n = 13), FLT3-ITD (n = 10), monosomy 7 (n = 5), TP53 (n = 3), Inv(3) (n = 3), IDH1/2 (n = 2), monosomy 5 (n = 1), NUP98 (n = 1) and ASXL1 (n = 1). The majority (86%) received venetoclax with a hypomethylating agent. Grade 3 or 4 adverse events included febrile neutropenia in 37% (n = 16), non-febrile neutropenia in 12% (n = 5), anemia in 14% (n = 6), and thrombocytopenia in 14% (n = 6). Of 40 patients evaluable for response, 10 patients (25%) achieved complete response (CR), 6 patients (15%) achieved CR with incomplete blood count recovery (CRi), and 2 patients (5%) had a partial response, (CR/CRi composite = 40%; ORR = 45%). Eleven (25%) patients received a hematopoietic stem cell transplant following venetoclax combination therapy, and six remain alive (median follow-up time 33.6 months). Median event-free survival and overall survival duration was 3.7 months and 8.7 months, respectively. Our findings suggest that in pediatric patients with AML, venetoclax is well-tolerated, with a safety profile similar to that in adults. More studies are needed to establish an optimal venetoclax-based regimen for the pediatric population.
    Keywords:  Bcl-2 inhibitor; acute myeloid leukemia; children; pediatric; venetoclax
    DOI:  https://doi.org/10.3390/cancers15071983
  9. Cancer. 2023 Apr 11.
    Phase 1/1b study of azacitidine and hedgehog pathway inhibitor sonidegib in patients with myeloid neoplasms.
    Raoul Tibes, Heidi E Kosiorek, Amylou C Dueck, Jeanne Palmer, Lisa Sproat, James Bogenberger, Shahrukh Hashmi, Ruben Mesa, William Hogan, Mark R Litzow, Aref Al-Kali.
       BACKGROUND: Myeloid neoplasms (myelodysplastic syndrome [MDS], myelofibrosis, and chronic myelomonocytic [CMML]) are aggressive hematological malignancies for which, despite recent approvals, novel therapies are needed to improve clinical outcomes. The hedgehog (HH) pathway is one of the main pathways for cancer stem cells survival and several HH inhibitors (HHi) are approved in clinical practice.
    METHODS: Sonidegib (SON), an oral HHi, was tested in this phase 1/1b trial in combination with azacitidine (AZA, 75 mg/m2 days ×7) in patients with newly diagnosed and relapsed/refractory (r/r) chronic MN or acute myeloid leukemia (AML).
    RESULTS: Sixty-two patients (28 [45%] newly diagnosed) were treated in this study, including 10 patients in the dose-finding component and 52 patients in phase 1b. SON 200 mg oral daily on days 1-28 each cycle was deemed the recommended dose for phase 1b. Out of 21 rrAML patients, two achieved response (one complete response/one morphologic leukemia-free state) with no responses seen in seven r/r MDS/CMML patients. In newly diagnosed AML/MDS, response was seen in six (three had complete remission, two had morphological leukemia-free status) of 27 patients. Median overall survival was 26.4 and 4.7 months for newly diagnosed MDS and AML, respectively. Safety was satisfactory with common (>20%) side effects including fatigue, constipation, nausea, cough, insomnia, and diarrhea. Only 7% of patients died in the study, and none of the deaths were deemed related to treatment.
    CONCLUSIONS: Our study shows that AZA + SON are a safe combination in a patient with MN. Similar to other hedgehog inhibitors, this combination yielded limited response rate in patients with myeloid neoplasms.
    Keywords:  AML; MDS; azacitidine; hedgehog inhibitor; sonidegib
    DOI:  https://doi.org/10.1002/cncr.34800
  10. Haematologica. 2023 Apr 13.
    Higher-dose venetoclax with measurable residual disease-guided azacitidine discontinuation in newly diagnosed acute myeloid leukemia.
    Jonathan A Gutman, Amanda Winters, Andrew Kent, Maria Amaya, Christine McMahon, Clayton Smith, Craig T Jordan, Brett Stevens, Mohammad Minhajuddin, Shanshan Pei, Jeffrey Schowinsky, Jennifer Tobin, Kelly O'Brien, Angela Falco, Elizabeth Taylor, Constance Brecl, Katie Zhou, Phuong Ho, Connor Sohalski, Jessica Dell-Martin, Olivia Ondracek, Diana Abbott, Daniel A Pollyea.
      Venetoclax+azacitidine is the standard of care for newly-diagnosed patients with acute myeloid leukemia (AML) for whom intensive chemotherapy is inappropriate. Efforts to optimize this regimen are necessary. We designed a clinical trial to investigate two hypotheses: 1)Higher doses of venetoclax are tolerable and more effective, and 2)Azacitidine can be discontinued after deep remissions. Forty-two newly-diagnosed AML patients were enrolled in the investigator-initiated High Dose Discontinuation Azacitidine + Venetoclax (HiDDAV) Study. Patients received 1-3 "induction" cycles of venetoclax 600mg daily with azacitidine. Responders received MRD-positive or negative "maintenance" arms: azacitidine with 400mg venetoclax or 400mg venetoclax alone, respectively. The toxicity profile of HiDDAV was similar to 400mg venetoclax. The overall response rate was 66.7%; the duration of response (DOR), event-free survival (EFS) and overall survival were 12.9, 7.8 and 9.8 months, respectively. The MRD-negativity rate was 64.3% by flow cytometry and 25.0% when also measured by droplet digital PCR. MRD-negative patients by flow cytometry had improved DOR and EFS; more stringent measures of MRD-negativity were not associated with improved OS, DOR or EFS. Using MRD to guide azacitidine discontinuation did not lead to improved DOR, EFS or OS compared to patients who discontinued azacitidine without MRD guidance. Within the context of this study design, venetoclax doses >400mg with azacitidine were well tolerated but not associated with discernible clinical improvement, and MRD may not assist in recommendations to discontinue azacitidine. Other strategies to optimize, and for some patients, de-intensify, venetoclax+azacitidine regimens are needed.
    DOI:  https://doi.org/10.3324/haematol.2023.282681
  11. Front Cell Dev Biol. 2023 ;11 1076458
    Dual inhibition of EZH2 and G9A/GLP histone methyltransferases by HKMTI-1-005 promotes differentiation of acute myeloid leukemia cells.
    Y Sbirkov, T Schenk, C Kwok, S Stengel, R Brown, G Brown, L Chesler, A Zelent, M J Fuchter, K Petrie.
      All-trans-retinoic acid (ATRA)-based differentiation therapy of acute promyelocytic leukemia (APL) represents one of the most clinically effective examples of precision medicine and the first example of targeted oncoprotein degradation. The success of ATRA in APL, however, remains to be translated to non-APL acute myeloid leukemia (AML). We previously showed that aberrant histone modifications, including histone H3 lysine 4 (H3K4) and lysine 27 (H3K27) methylation, were associated with this lack of response and that epigenetic therapy with small molecule inhibitors of the H3K4 demethylase LSD1/KDM1A could reprogram AML cells to respond to ATRA. Serving as the enzymatic component of Polycomb Repressive Complex 2, EZH2/KMT6A methyltransferase plays a critical role in normal hematopoiesis by affecting the balance between self-renewal and differentiation. The canonical function of EZH2 is methylation of H3K27, although important non-canonical roles have recently been described. EZH2 mutation or deregulated expression has been conclusively demonstrated in the pathogenesis of AML and response to treatment, thus making it an attractive therapeutic target. In this study, we therefore investigated whether inhibition of EZH2 might also improve the response of non-APL AML cells to ATRA-based therapy. We focused on GSK-343, a pyridone-containing S-adenosyl-L-methionine cofactor-competitive EZH2 inhibitor that is representative of its class, and HKMTI-1-005, a substrate-competitive dual inhibitor targeting EZH2 and the closely related G9A/GLP H3K9 methyltransferases. We found that treatment with HKMTI-1-005 phenocopied EZH2 knockdown and was more effective in inducing differentiation than GSK-343, despite the efficacy of GSK-343 in terms of abolishing H3K27 trimethylation. Furthermore, transcriptomic analysis revealed that in contrast to treatment with GSK-343, HKMTI-1-005 upregulated the expression of differentiation pathway genes with and without ATRA, while downregulating genes associated with a hematopoietic stem cell phenotype. These results pointed to a non-canonical role for EZH2, which was supported by the finding that EZH2 associates with the master regulator of myeloid differentiation, RARα, in an ATRA-dependent manner that was enhanced by HKMTI-1-005, possibly playing a role in co-regulator complex exchange during transcriptional activation. In summary, our results strongly suggest that addition of HKMTI-1-005 to ATRA is a new therapeutic approach against AML that warrants further investigation.
    Keywords:  EZH2/KMT6A; G9A/EHMT2; GLP/EHMT1; HKMTI-1-005; RARα; acute myeloid leukemia (AML); all-trans retinoic acid (ATRA); differentiation
    DOI:  https://doi.org/10.3389/fcell.2023.1076458
  12. Nat Commun. 2023 Apr 08. 14(1): 1979
    MOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins.
    Yosuke Komata, Akinori Kanai, Takahiro Maeda, Toshiya Inaba, Akihiko Yokoyama.
      Changes in the transcriptional machinery cause aberrant self-renewal of non-stem hematopoietic progenitors. AF10 fusions, such as CALM-AF10, are generated via chromosomal translocations, causing malignant leukemia. In this study, we demonstrate that AF10 fusion proteins cause aberrant self-renewal via ENL, which binds to MOZ/MORF lysine acetyltransferases (KATs). The interaction of ENL with MOZ, via its YEATS domain, is critical for CALM-AF10-mediated leukemic transformation. The MOZ/ENL complex recruits DOT1L/AF10 fusion complexes and maintains their chromatin retention via KAT activity. Therefore, inhibitors of MOZ/MORF KATs directly suppress the functions of AF10 fusion proteins, thereby exhibiting strong antitumor effects on AF10 translocation-induced leukemia. Combinatorial inhibition of MOZ/MORF and DOT1L cooperatively induces differentiation of CALM-AF10-leukemia cells. These results reveal roles for the MOZ/ENL complex as an essential recruiting factor of the AF10 fusion/DOT1L complex, providing a rationale for using MOZ/MORF KAT inhibitors in AF10 translocation-induced leukemia.
    DOI:  https://doi.org/10.1038/s41467-023-37712-5
  13. Nature. 2023 Apr 12.
    Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.
    NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
      Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2-6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.
    DOI:  https://doi.org/10.1038/s41586-023-05806-1
  14. Blood Cancer J. 2023 04 11. 13(1): 51
    TP53 mutation variant allele frequency of ≥10% is associated with poor prognosis in therapy-related myeloid neoplasms.
    Mithun Vinod Shah, Elizabeth Ngoc Hoa Tran, Syed Shah, Rakchha Chhetri, Anmol Baranwal, Dariusz Ladon, Carl Shultz, Aref Al-Kali, Anna L Brown, Dong Chen, Hamish S Scott, Patricia Greipp, Daniel Thomas, Hassan B Alkhateeb, Deepak Singhal, Naseema Gangat, Sharad Kumar, Mrinal M Patnaik, Christopher N Hahn, Chung Hoow Kok, Ayalew Tefferi, Devendra K Hiwase.
      Revised diagnostic criteria for myeloid neoplasms (MN) issued by the International Consensus Classification (ICC) and the World Health Organization (WHO) recommended major change pertaining to TP53-mutated (TP53mut) MN. However, these assertions have not been specifically examined in therapy-related myeloid neoplasm (t-MN), a subset enriched with TP53mut. We analyzed 488 t-MN patients for TP53mut. At least one TP53mut with variant allele frequency (VAF) ≥ 2% with or without loss of TP53 locus was noted in 182 (37.3%) patients and 88.2% of TP53mut t-MN had a VAF ≥10%. TP53mut t-MN with VAF ≥ 10% had a distinct clinical and biological profile compared to both TP53mut VAF < 10% and wild-type TP53 (TP53wt) cases. Notably, TP53mut VAF ≥ 10% had a significantly shorter survival compared to TP53wt (8.3 vs. 21.6 months; P < 0.001), while the survival of TP53mut VAF < 10% was comparable to TP53wt. Within TP53mut VAF ≥ 10% cohort, the inferior outcomes persisted irrespective of the single- or multi-hit status, co-mutation pattern, or treatments received. Finally, survival of TP53mut patients was poor across all the blast categories and MDS patients with >10% blasts had inferior survival compared to <5%. In summary, TP53mut VAF ≥10% signified a clinically and molecularly homogenous cohort regardless of the allelic status.
    DOI:  https://doi.org/10.1038/s41408-023-00821-x
  15. Blood Adv. 2023 Apr 12. pii: bloodadvances.2023009818. [Epub ahead of print]
    Statin Use in Myelodysplastic Syndromes Is Associated with a Better Survival and Decreased Progression to Leukemia.
    Amber Afzal, Mark A Fiala, Meagan A Jacoby, Matthew J Walter.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2023009818
  16. Curr Hematol Malig Rep. 2023 Apr 13.
    Therapeutic Targets in Myelodysplastic Neoplasms: Beyond Hypomethylating Agents.
    Prateek Pophali, Sudhamsh Reddy Desai, Aditi Shastri.
       PURPOSE OF REVIEW: To discuss novel targeted therapies under investigation for treatment of myelodysplastic neoplasms (MDS).
    RECENT FINDINGS: Over the last few years, results of phase 3 trials assessing novel therapies for high-risk MDS have been largely disappointing. Pevonedistat (NEDD-8 inhibitor) and APR-246 (TP53 reactivator) both did not meet trial endpoints. However, early phase trials of BCL-2, TIM3, and CD47 inhibitors have shown exciting data and are currently under phase 3 investigation. Moreover, combination of hypomethylating agents (HMA) with novel therapies targeting the mutational (IDH, FLT3, spliceosome complex) or immune (PD-1/PDL-1, TIM-3, IRAK-4) pathways are being investigated in early phase clinical trials and have shown adequate safety and promising efficacy. Myelodysplastic neoplasms (MDS) are a group of hematopoietic neoplasms defined by cytopenias and morphological dysplasia. They are characterized by clonal proliferation of aberrant hematopoietic stem cells caused by recurrent genetic abnormalities. This leads to ineffective erythropoiesis, peripheral blood cytopenias, abnormal cell maturation, and a high risk of transformation into acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation is the only curative therapy; however, it is not a suitable option for majority patients due to their age, comorbidities, and the high rate of treatment-related complications. HMAs remain the only FDA-approved treatment option for high-risk MDS. Due to intolerance, primary, and secondary resistance to HMA, there is a large unmet need to develop new safe and effective therapies for patients with MDS. In this review, we focus on the current management strategies and novel therapies in development for treatment of high-risk MDS.
    Keywords:  Hypomethylating agents; Myelodysplastic syndromes; Targeted therapies
    DOI:  https://doi.org/10.1007/s11899-023-00693-9
  17. Nat Commun. 2023 Apr 12. 14(1): 2070
    Inflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis.
    N Zioni, A Akhiad Bercovich, N Chapal-Ilani, Tal Bacharach, N Rappoport, A Solomon, R Avraham, E Kopitman, Z Porat, M Sacma, G Hartmut, M Scheller, C Muller-Tidow, D Lipka, E Shlush, M Minden, N Kaushansky, Liran I Shlush.
      Both fatty bone marrow (FBM) and somatic mutations in hematopoietic stem cells (HSCs), also termed clonal hematopoiesis (CH) accumulate with human aging. However it remains unclear whether FBM can modify the evolution of CH. To address this question, we herein present the interaction between CH and FBM in two preclinical male mouse models: after sub-lethal irradiation or after castration. An adipogenesis inhibitor (PPARγ inhibitor) is used in both models as a control. A significant increase in self-renewal can be detected in both human and rodent DNMT3AMut-HSCs when exposed to FBM. DNMT3AMut-HSCs derived from older mice interacting with FBM have even higher self-renewal in comparison to DNMT3AMut-HSCs derived from younger mice. Single cell RNA-sequencing on rodent HSCs after exposing them to FBM reveal a 6-10 fold increase in DNMT3AMut-HSCs and an activated inflammatory signaling. Cytokine analysis of BM fluid and BM derived adipocytes grown in vitro demonstrates an increased IL-6 levels under FBM conditions. Anti-IL-6 neutralizing antibodies significantly reduce the selective advantage of DNMT3AMut-HSCs exposed to FBM. Overall, paracrine FBM inflammatory signals promote DNMT3A-driven clonal hematopoiesis, which can be inhibited by blocking the IL-6 pathway.
    DOI:  https://doi.org/10.1038/s41467-023-36906-1
  18. Blood Adv. 2023 Apr 14. pii: bloodadvances.2022009493. [Epub ahead of print]
    Posttransplant MRD and T-cell chimerism status predict outcomes in patients allografted with AML/MDS.
    Justin Loke, Nicholas McCarthy, Aimee E Jackson, Shamyla Siddique, Andrea Hodgkinson, John Mason, Charles R Crawley, Maria Gilleece, Andrew J Peniket, Rachel Protheroe, Rahuman Salim, Eleni Tholouli, Keith WIlson, Georgia Andrew, Richard Dillon, Naeem Khan, Victoria Potter, Pramila Krishnamurthy, Charles Craddock, Sylvie D Freeman.
      Allogeneic stem-cell transplantation allows the delivery of curative graft-versus-leukemia (GVL) in patients with acute myeloid leukemia/myelodysplasia (AML/MDS). Surveillance of T-cell chimerism, measurable residual disease (MRD) and blast HLA-DR expression may inform whether GVL effectiveness is reduced. We report the prognostic impact of these biomarkers in patients allografted for AML/MDS. 187 patients from FIGARO, a randomized trial of reduced-intensity conditioning regimens in AML/MDS, were alive and relapse-free, at the first MRD timepoint and provided bone marrow for flow cytometric MRD monitoring and blood samples for T-cell chimerism analysis, requested to month+12. 29 (15.5%) patients had at least one MRD-positive result post-transplant. MRD-positivity was associated with reduced overall survival (OS) (HR:2.18, p=0.0028) as a time-varying Cox variable and remained significant irrespective of pre-transplant MRD status in multivariate analyses (p<0.001). 94 patients had sequential MRD with T-cell chimerism results at months+3/+6. Patients with full donor T-cell chimerism (FDTC) had an improved OS as compared with patients with mixed-donor T-cell chimerism (MDTC) (adjusted-HR=0.4, p=0.0019). In patients with MDTC (month+3 or +6), MRD-positivity was associated with decreased 2yr-OS (34.3% [95% CI:11.6-58.7] versus MRD-negative 71.4% [95% CI:52.2-84.0], p=0.001). In contrast, in the group with FDTC, MRD was infrequent and did not impact outcome. Amongst patients with post-transplant MRD-positivity, decreased HLA-DR expression on blasts significantly reduced OS, supporting this as a mechanism for GVL escape. Post-transplant MRD is an important predictor of outcome in patients allografted for AML/MDS and is most informative when combined with T-cell chimerism results, underlining the importance of a GVL effect in AML/MDS.
    DOI:  https://doi.org/10.1182/bloodadvances.2022009493
  19. Blood. 2023 Apr 13. pii: blood.2023020108. [Epub ahead of print]
    IPSS-M in myelodysplastic neoplasms arising from aplastic anemia and paroxysmal nocturnal hemoglobinuria.
    Carmelo Gurnari, Pedro Henrique Prata, Luiz Fernando B Catto, Arda Durmaz, Lise Larcher, Marie Sébert, Vincent Allain, Tariq Kewan, Simona Pagliuca, André Luiz Pinto, Mariana C B Inacio, Lucie Hernandez, Nathalie Dhedin, Sophie Caillat-Zucman, Emmanuelle Clappier, Flore Sicre de Fontbrune, Maria Teresa Voso, Valeria Visconte, Régis Peffault de Latour, Jean Soulier, Gérard Socie, Rodrigo T Calado, Jaroslaw P Maciejewski.
      
    DOI:  https://doi.org/10.1182/blood.2023020108
  20. Sci Adv. 2023 Apr 14. 9(15): eadf8522
    M2 macrophages drive leukemic transformation by imposing resistance to phagocytosis and improving mitochondrial metabolism.
    Isabel Weinhäuser, Diego A Pereira-Martins, Luciana Y Almeida, Jacobien R Hilberink, Douglas R A Silveira, Lynn Quek, Cesar Ortiz, Cleide L Araujo, Thiago M Bianco, Antonio Lucena-Araujo, Jose Mauricio Mota, Shanna M Hogeling, Dominique Sternadt, Nienke Visser, Arjan Diepstra, Emanuele Ammatuna, Gerwin Huls, Eduardo M Rego, Jan Jacob Schuringa.
      It is increasingly becoming clear that cancers are a symbiosis of diverse cell types and tumor clones. Combined single-cell RNA sequencing, flow cytometry, and immunohistochemistry studies of the innate immune compartment in the bone marrow of patients with acute myeloid leukemia (AML) reveal a shift toward a tumor-supportive M2-polarized macrophage landscape with an altered transcriptional program, with enhanced fatty acid oxidation and NAD+ generation. Functionally, these AML-associated macrophages display decreased phagocytic activity and intra-bone marrow coinjection of M2 macrophages together with leukemic blasts strongly enhances in vivo transformation potential. A 2-day in vitro exposure to M2 macrophages results in the accumulation of CALRlow leukemic blast cells, which are now protected against phagocytosis. Moreover, M2-exposed "trained" leukemic blasts display increased mitochondrial metabolism, in part mediated via mitochondrial transfer. Our study provides insight into the mechanisms by which the immune landscape contributes to aggressive leukemia development and provides alternatives for targeting strategies aimed at the tumor microenvironment.
    DOI:  https://doi.org/10.1126/sciadv.adf8522
  21. Proc Natl Acad Sci U S A. 2023 Apr 18. 120(16): e2220134120
    Interrogating bromodomain inhibitor resistance in KMT2A-rearranged leukemia through combinatorial CRISPR screens.
    Shaela Wright, Jianzhong Hu, Hong Wang, Judith Hyle, Yang Zhang, Guoqing Du, Marina Y Konopleva, Steven M Kornblau, Mohamed Nadhir Djekidel, Wojciech Rosikiewicz, Beisi Xu, Rui Lu, Jun J Yang, Chunliang Li.
      Bromo- and extra-terminal domain inhibitors (BETi) have exhibited therapeutic activities in many cancers. However, the mechanisms controlling BETi response and resistance are not well understood. We conducted genome-wide loss-of-function CRISPR screens using BETi-treated KMT2A-rearranged (KMT2A-r) cell lines. We revealed that Speckle-type POZ protein (SPOP) gene (Speckle Type BTB/POZ Protein) deficiency caused significant BETi resistance, which was further validated in cell lines and xenograft models. Proteomics analysis and a kinase-vulnerability CRISPR screen indicated that cells treated with BETi are sensitive to GSK3 perturbation. Pharmaceutical inhibition of GSK3 reversed the BETi-resistance phenotype. Based on this observation, a combination therapy regimen inhibiting both BET and GSK3 was developed to impede KMT2A-r leukemia progression in patient-derived xenografts in vivo. Our results revealed molecular mechanisms underlying BETi resistance and a promising combination treatment regimen of ABBV-744 and CHIR-98014 by utilizing unique ex vivo and in vivo KMT2A-r PDX models.
    Keywords:  KMT2A-rearranged leukemia; SPOP; bromodomain inhibitor; genome editing
    DOI:  https://doi.org/10.1073/pnas.2220134120
  22. Blood Adv. 2023 Apr 12. pii: bloodadvances.2022009478. [Epub ahead of print]
    Alemtuzumab and CXCL9 levels predict likelihood of sustained engraftment after reduced intensity conditioning HCT.
    Ashley V Geerlinks, Brooks Scull, Christa Krupski, Ryan Fleischmann, Michael A Pulsipher, Mary Eapen, James A Connelly, Catherine M Bollard, Sung-Yun Pai, Christine Duncan, Leslie S Kean, K Scott Baker, Lauri Burroughs, Jeffrey R Andolina, Shalini Shenoy, Philip Roehrs, Rabi Hanna, Julie-An Talano, Kirk R Schultz, Elizabeth O Stenger, Howard Lin, Adi Zoref-Lorenz, Kenneth L McClain, Michael B Jordan, Tsz-Kwong Man, Carl E Allen, Rebecca A Marsh.
      Overall survival following reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) using alemtuzumab, fludarabine, and melphalan is favorable in patients transplanted for inborn errors of immunity (IEI), but RIC is associated with high rates of mixed chimerism (MC) and secondary graft failure (GF). We hypothesized that peri-transplant alemtuzumab levels or specific patterns of inflammation would predict these risks. We assessed samples from BMT CTN 1204 (NCT01998633) to study the impact of alemtuzumab levels and cytokine patterns on MC and impending or established secondary GF (defined as donor chimerism <5% after initial engraftment and/or requirement of cellular intervention). Thirty-three patients with HLH (n=25) and other IEI (n=8) who underwent HCT with T-cell replete grafts were included. Patients with day 0 alemtuzumab levels ≤0.32μg/mL had a markedly lower incidence of MC, 14.3%, versus 90.9% in patients >0.32μg/mL (p=0.008). Impending or established secondary GF was only observed in patients with day 0 alemtuzumab levels >0.32µg/mL (p=0.08). Unexpectedly, patients with impending or established secondary GF had lower CXCL9 levels. The cumulative incidence of impending or established secondary GF in patients with a day +14 CXCL9 level ≤2394pg/mL (day +14 median) was 73.6% versus 0% in patients >2394pg/mL (p=0.002). CXCL9 levels inversely correlated with alemtuzumab levels. These findings support a relationship between alemtuzumab levels, CXCL9 levels, and sustained engraftment. These data suggest a model in which higher levels of alemtuzumab at day 0 deplete donor T-cells, inhibit the graft-versus-marrow reaction (thereby suppressing CXCL9 levels), and adversely impact sustained engraftment in the non-myeloablative HCT setting. Clinical Trial # NCT01998633.
    DOI:  https://doi.org/10.1182/bloodadvances.2022009478
  23. medRxiv. 2023 Mar 27. pii: 2023.03.26.23287367. [Epub ahead of print]
    Quantification of measurable residual disease using duplex sequencing in adults with acute myeloid leukemia.
    Laura W Dillon, Jake Higgins, Hassan Nasif, Megan Othus, Lan Beppu, Thomas H Smith, Elizabeth Schmidt, Charles C Valentine, Jesse J Salk, Brent L Wood, Harry P Erba, Jerald P Radich, Christopher S Hourigan.
      The presence of measurable residual disease (MRD) is strongly associated with treatment outcomes in acute myeloid leukemia (AML). Despite the correlation with clinical outcomes, MRD assessment has yet to be standardized or routinely incorporated into clinical trials. Discrepancies have been observed between different techniques for MRD assessment and there remains a need to compare centralized, high-quality multiparametric flow cytometry (MFC) and ultrasensitive next-generation sequencing (NGS) in AML patients with diverse mutational profiles. In 62 patients with AML, aged 18-60, in first complete remission after intensive induction therapy on the randomized phase 3 SWOG-S0106 clinical trial, MRD detection by MFC was compared with a 29 gene panel utilizing duplex sequencing (DS), an NGS method that generates double-stranded consensus sequences to reduce false positive errors. Using DS, detection of a persistent mutation utilizing defined criteria was seen in 22 (35%) patients and was strongly associated with higher rates of relapse (68% vs 13% at year 5; HR, 8.8; 95% CI, 3.2-24.5; P<0.001) and decreased survival (32% vs 82% at year 5; HR, 5.6; 95% CI, 2.3-13.8; P<0.001). MRD as defined by DS strongly outperformed MFC, which was observed in 10 (16%) patients and marginally associated with higher rates of relapse (50% vs 30% at year 5; HR, 2.4; 95% CI, 0.9-6.7; P=0.087) and decreased survival (40% vs 68% at year 5; HR, 2.5; 95% CI, 1.0-6.3; P=0.059). Furthermore, the prognostic significance of DS MRD status at the time of remission was similar on both randomized arms of the trial, predicting S0106 clinical trial outcomes. These findings suggest that DS is a powerful tool that could be used in patient management and for early treatment assessment in clinical trials.
    DOI:  https://doi.org/10.1101/2023.03.26.23287367
  24. JCO Oncol Pract. 2023 Apr 14. OP2200822
    Outcomes of Older Adults With AML Treated in Community Versus Academic Centers: An Analysis of Alliance Trials.
    Vijaya Raj Bhatt, Angela M Ulrich, Geoffrey L Uy, Richard M Stone, Wendy Stock, Michael O Ojelabi, Jun Yin, Jessica Kohlschmidt, Ann-Kathrin Eisfeld, Maria R Baer, Selina Chow, Heidi Klepin, Jennifer Le-Rademacher, Aminah Jatoi.
       PURPOSE: Clinical trials are important for managing older patients with AML. We investigated differences in outcomes of older patients with AML on the basis of whether patients participated in intensive chemotherapy trials at community versus academic cancer centers.
    METHODS: We used data from the Alliance for Clinical Trials in Oncology phase III trials that enrolled patients age ≥ 60 years with newly diagnosed AML between 1998 and 2002 in the Cancer and Leukemia Group B (CALGB) 9720 trial and between 2004 and 2006 in the CALGB 10201 trial. Centers funded by the NCI Community Oncology Research Program were identified as community cancer centers; others were designated as academic cancer centers. Logistic regression models and Cox proportional hazards models were used to compare 1-month mortality and overall survival (OS) by center type.
    RESULTS: Seventeen percent of the 1,170 patients were enrolled in clinical trials in community cancer centers. The study results demonstrated comparable rates of grade ≥3 adverse events (97% v 93%), 1-month mortality (19.1% v 16.1%), and OS (43.9% v 35.7% at 1 year) between community versus academic cancer centers, respectively. After adjusting for covariates, 1-month mortality (odds ratio, 1.40; 95% CI, 0.92 to 2.12; P = .11) and OS (hazard ratio, 1.04; 95% CI, 0.88 to 1.22; P = .67) were not statistically different among patients treated in community versus academic cancer centers.
    CONCLUSION: An older patient population, who have complex health care needs, can be successfully treated on intensive chemotherapy trials in select community cancer centers with outcomes comparable with that achieved at academic cancer centers.
    DOI:  https://doi.org/10.1200/OP.22.00822
  25. Br J Haematol. 2023 Apr 14.
    Transcriptional and genomic characterization of measurable residual disease in acute myeloid leukaemia.
    PETHEMA cooperative study group
      
    DOI:  https://doi.org/10.1111/bjh.18815
  26. Cancer Immunol Immunother. 2023 Apr 11.
    CD33 BiTE® molecule-mediated immune synapse formation and subsequent T-cell activation is determined by the expression profile of activating and inhibitory checkpoint molecules on AML cells.
    Anetta Marcinek, Bettina Brauchle, Lisa Rohrbacher, Gerulf Hänel, Nora Philipp, Florian Märkl, Thaddäus Strzalkowski, Sonja M Lacher, Dragica Udiljak, Karsten Spiekermann, Sebastian Theurich, Sebastian Kobold, Roman Kischel, John R James, Veit L Bücklein, Marion Subklewe.
      Bispecific T-cell engager (BiTE®) molecules recruit T cells to cancer cells through CD3ε binding, independently of T-cell receptor (TCR) specificity. Whereas physiological T-cell activation is dependent on signal 1 (TCR engagement) and signal 2 (co-stimulation), BiTE molecule-mediated T-cell activation occurs without additional co-stimulation. As co-stimulatory and inhibitory molecules modulate the strength and nature of T-cell responses, we studied the impact of the expression profile of those molecules on target cells for BiTE molecule-mediated T-cell activation in the context of acute myeloid leukemia (AML). Accordingly, we created a novel in vitro model system using murine Ba/F3 cells transduced with human CD33 ± CD86 ± PD-L1. T-cell fitness was assessed by T-cell function assays in co-cultures and immune synapse formation by applying a CD33 BiTE molecule (AMG 330). Using our cell-based model platform, we found that the expression of positive co-stimulatory molecules on target cells markedly enhanced BiTE molecule-mediated T-cell activation. The initiation and stability of the immune synapse between T cells and target cells were significantly increased through the expression of CD86 on target cells. By contrast, the co-inhibitory molecule PD-L1 impaired the stability of BiTE molecule-induced immune synapses and subsequent T-cell responses. We validated our findings in primary T-cell-AML co-cultures, demonstrating a PD-L1-mediated reduction in redirected T-cell activation. The addition of the immunomodulatory drug (IMiD) lenalidomide to co-cultures led to stabilization of immune synapses and improved subsequent T-cell responses. We conclude that target cells modulate CD33 BiTE molecule-dependent T-cell activation and hence, combinatorial strategies might contribute to enhanced efficacy.
    Keywords:  Acute myeloid leukemia; Bispecific antibodies; Checkpoint molecule (PD-L1); Costimulation (CD86); Immune synapse
    DOI:  https://doi.org/10.1007/s00262-023-03439-x
  27. J Natl Cancer Inst. 2023 Apr 12. pii: djad065. [Epub ahead of print]
    Clonal Hematopoiesis in Older Patients with Breast Cancer Receiving Chemotherapy.
    Christina Mayerhofer, Mina S Sedrak, Judith O Hopkins, Tianyu Li, Nabihah Tayob, Meredith G Faggen, Natalie F Sinclair, Wendy Y Chen, Heather A Parsons, Erica L Mayer, Paulina B Lange, Ameer S Basta, Adriana Perilla-Glen, Ruth I Lederman, Andrew R Wong, Abhay Tiwari, Sandra S McAllister, Elizabeth A Mittendorf, Christopher J Gibson, Harold J Burstein, Annette S Kim, Rachel A Freedman, Peter G Miller.
       BACKGROUND: The expansion of hematopoietic stem cells carrying recurrent somatic mutations, termed clonal hematopoiesis (CH), is common in elderly individuals and associated with increased risk of myeloid malignancy and all-cause mortality. Though chemotherapy is a known risk factor for developing CH, how myelosuppressive therapies affect the short-term dynamics of CH remains incompletely understood. Most studies have been limited by retrospective design, heterogeneous patient populations, varied techniques to identifying CH, and analysis of single time points.
    METHODS: We examined serial samples from 40 older females with triple-negative or hormone receptor-positive breast cancer treated on the prospective ADjuVANt Chemotherapy in the Elderly (ADVANCE) trial to evaluate the prevalence and dynamics of CH at baseline and throughout chemotherapy (6 and 12 weeks).
    RESULTS: CH was detected in 44% of patients at baseline and in 53% at any timepoint. Baseline patient characteristics were not associated with CH. Over the course of treatment, mutations exhibited a variety of dynamics, including emergence, expansion, contraction, and disappearance. All mutations in TP53 (n = 3) and PPM1D (n = 4), genes that regulate the DNA damage response, either became detectable or expanded over the course of treatment. Neutropenia was more common in patients with CH, particularly when the mutations became detectable during treatment, and CH was significantly associated with cyclophosphamide dose reductions and holds (p = .02).
    CONCLUSIONS: Our study shows that CH is common, dynamic, and of potential clinical significance in this population. Our results should stimulate larger efforts to understand the biological and clinical importance of CH in solid tumor malignancies.
    TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT03858322). Clinical trial registration number: NCT03858322.
    DOI:  https://doi.org/10.1093/jnci/djad065
  28. bioRxiv. 2023 Mar 28. pii: 2023.03.27.534395. [Epub ahead of print]
    Therapeutic targeting of ACLY in T-ALL in vivo.
    Victoria da Silva-Diz, Amartya Singh, Olga Lancho, Maya Aleksandrova, Komal Mandleywala, Patricia Renck Nunes, Jesminara Khatun, Oekyung Kim, Eric Chiles, Xiaoyang Su, Hossein Khiabanian, Kathryn E Wellen, Daniel Herranz.
      T-cell Acute Lymphoblastic Leukemia (T-ALL) is a hematological malignancy in need of novel therapeutic approaches. Here, we identify the ATP-citrate lyase ACLY as a novel therapeutic target in T-ALL. Our results show that ACLY is overexpressed in T-ALL, and its expression correlates with NOTCH1 activity. To test the effects of ACLY in leukemia progression and the response to NOTCH1 inhibition, we developed an isogenic model of NOTCH1-induced Acly conditional knockout leukemia. Importantly, we observed intrinsic antileukemic effects upon loss of ACLY, which further synergized with NOTCH1 inhibition in vivo . Gene expression profiling analyses showed that the transcriptional signature of ACLY loss very significantly correlates with the signature of NOTCH1 inhibition in vivo , with significantly downregulated pathways related to oxidative phosphorylation, electron transport chain, ribosomal biogenesis and nucleosome biology. Consistently, metabolomic profiling upon ACLY loss revealed a metabolic crisis with accumulation of nucleotide intermediates and reduced levels of several amino acids. Overall, our results identify a link between NOTCH1 and ACLY and unveil ACLY as a novel promising target for T-ALL treatment.
    DOI:  https://doi.org/10.1101/2023.03.27.534395
  29. Blood. 2023 Apr 13. 141(15): 1896
    Stein EM. IDH2 inhibition in AML. Blood. 2023;141(2):124-125.
      
    DOI:  https://doi.org/10.1182/blood.2023020034
  30. Redox Biol. 2023 Apr 02. pii: S2213-2317(23)00093-9. [Epub ahead of print]62 102692
    Emerging drugs targeting cellular redox homeostasis to eliminate acute myeloid leukemia stem cells.
    Rafaela G A Costa, Suellen L R Silva, Ingrid R S B Dias, Maiara de S Oliveira, Ana Carolina B da C Rodrigues, Rosane B Dias, Daniel P Bezerra.
      Acute myeloid leukemia (AML) is a very heterogeneous group of disorders with large differences in the percentage of immature blasts that presently are classified according to the specific mutations that trigger malignant proliferation among thousands of mutations reported thus far. It is an aggressive disease for which few targeted therapies are available and still has a high recurrence rate and low overall survival. The main reason for AML relapse is believed to be due to leukemic stem cells (LSCs) that have unlimited self-renewal capacity and long residence in a quiescent state, which promote greater resistance to traditional therapies for this cancer. AML LSCs have low oxidative stress levels, which appear to be caused by a combination of low mitochondrial activity and high activity of ROS-removing pathways. In this sense, oxidative stress has been thought to be an important new potential target for the treatment of AML patients, targeting the eradication of AML LSCs. The aim of this review is to discuss some drugs that induce oxidative stress to direct new goals for future research focusing on redox imbalance as an effective strategy to eliminate AML LSCs.
    Keywords:  Acute myeloid leukemia; Leukemia stem cells; Oxidative stress
    DOI:  https://doi.org/10.1016/j.redox.2023.102692
  31. Blood Adv. 2023 Apr 14. pii: bloodadvances.2022009534. [Epub ahead of print]
    Clinical Impact of Minimal Residual Disease in Blood and Bone Marrow of Children with Acute Myeloid Leukemia.
    Seth E Karol, Elaine Coustan-Smith, Stanley B Pounds, Lei Wang, Hiroto Inaba, Raul C Ribeiro, Ching-Hong Pui, Jeffery M Klco, Jeffrey E Rubnitz.
      The prognostic significance of bone marrow minimal residual disease (MRD) in pediatric patients with acute myeloid leukemia (AML) is well-characterized, but the impact of blood MRD is not known. We therefore used flow-cytometric assessment of leukemia-specific immunophenotypes to measure levels of MRD in both blood and bone marrow of patients treated on the AML08 (NCT00703820) clinical trial. Blood samples were obtained at days 8 and 22 of therapy, whereas bone marrow samples were obtained at day 22. Among patients who were MRD-negative in the bone marrow at day 22, neither day 8 nor day 22 blood MRD was significantly associated with outcome. However, day 8 blood MRD was highly predictive of outcome among patients who were bone marrow MRD-positive at day 22. Although the measurement of blood MRD at day 8 cannot be used to detect day 22 bone marrow MRD-negative patients who are likely to relapse, our findings suggest that day 8 blood MRD can identify bone marrow MRD-positive patients who have a dismal prognosis and who may be candidates for the early use of experimental therapy.
    DOI:  https://doi.org/10.1182/bloodadvances.2022009534
  32. Nat Commun. 2023 Apr 10. 14(1): 2018
    Restoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response.
    Pradeep Ramalingam, Michael C Gutkin, Michael G Poulos, Taylor Tillery, Chelsea Doughty, Agatha Winiarski, Ana G Freire, Shahin Rafii, David Redmond, Jason M Butler.
      Aging associated defects within stem cell-supportive niches contribute towards age-related decline in stem cell activity. However, mechanisms underlying age-related niche defects, and whether restoring niche function can improve stem cell fitness, remain unclear. Here, we sought to determine whether aged blood stem cell function can be restored by rejuvenating their supportive niches within the bone marrow (BM). We identify Netrin-1 as a critical regulator of BM niche cell aging. Niche-specific deletion of Netrin-1 induces premature aging phenotypes within the BM microenvironment, while supplementation of aged mice with Netrin-1 rejuvenates aged niche cells and restores competitive fitness of aged blood stem cells to youthful levels. We show that Netrin-1 plays an essential role in maintaining active DNA damage responses (DDR), and that aging-associated decline in niche-derived Netrin-1 results in DNA damage accumulation within the BM microenvironment. We show that Netrin-1 supplementation is sufficient to resolve DNA damage and restore regenerative potential of the aged BM niche and blood stem cells to endure serial chemotherapy regimens.
    DOI:  https://doi.org/10.1038/s41467-023-37783-4
  33. Ann Hematol. 2023 Apr 11.
    Outcome of patients with newly diagnosed AML admitted to the ICU, including preemptive admission - a multi-center study.
    Christophe Desprez, Achille Kouatchet, Tony Marchand, Jean Baptiste Mear, Jean Marc Tadié, Pierre Peterlin, Patrice Chevalier, Emmanuel Canet, Marie-Anne Couturier, Gaelle Guillerm, Laetitia Bodenes, Emmanuel Gyan, Alban Villate, Stephan Ehrmann, Anne Lebreton, Marie-Antoinette Lester, Clémentine Fronteau, Gaelle Larhantec, Virginie André, Jérémie Riou, Mathilde Hunault-Berger, Aline Schmidt-Tanguy, Corentin Orvain.
      Acute myeloid leukemia (AML) can lead to life-threatening complications that may require intensive care unit (ICU) management. It has been advocated that early preemptive (ePE) ICU admission, before the onset of organ failure, could benefit some high-risk patients such as those with hyperleukocytosis. The aim of this study was to retrospectively analyze the outcome of newly diagnosed AML patients who required ICU admission in five academic centers with a special focus on patients with an ePE admission strategy, i.e., those transferred to the ICU without any organ failure (modified SOFA score ≤ 2 [omitting thrombocytopenia] and no life-sustaining intervention in the first 24 h following ICU admission) before the start of induction therapy. Between January 2017 and December 2019, 428 patients were included among which 101 were admitted to the ICU. Among patients requiring life-sustaining interventions (n = 83), 18 (22%) died while in the ICU but ICU survivors had the same survival as those not admitted to the ICU. Patients with an ePE admission (n = 18) had more comorbidities and high-risk disease features such as hyperleukocytosis but required no life-sustaining interventions while in the ICU. In a subgroup analysis of patients with hyperleukocytosis ≥ 50 G/l at diagnosis (n = 85), patients not admitted to the ICU and those admitted with an ePE strategy had similar outcomes. This study provides encouraging results about ICU outcome in AML patients during induction therapy but the potential benefit of an ePE strategy must be confirmed prospectively.
    Keywords:  Acute myeloid leukemia; Early pre-emptive admission; Hyperleukocytosis; Induction chemotherapy; Intensive care unit
    DOI:  https://doi.org/10.1007/s00277-023-05205-6
  34. Blood Cancer Discov. 2023 Apr 13. OF1-OF13
    The Role of Inflammation in the Initiation and Progression of Myeloid Neoplasms.
    Juan Carlos Balandrán, Audrey Lasry, Iannis Aifantis.
      Myeloid malignancies are devastating hematologic cancers with limited therapeutic options. Inflammation is emerging as a novel driver of myeloid malignancy, with important implications for tumor composition, immune response, therapeutic options, and patient survival. Here, we discuss the role of inflammation in normal and malignant hematopoiesis, from clonal hematopoiesis to full-blown myeloid leukemia. We discuss how inflammation shapes clonal output from hematopoietic stem cells, how inflammation alters the immune microenvironment in the bone marrow, and novel therapies aimed at targeting inflammation in myeloid disease.
    SIGNIFICANCE: Inflammation is emerging as an important factor in myeloid malignancies. Understanding the role of inflammation in myeloid transformation, and the interplay between inflammation and other drivers of leukemogenesis, may yield novel avenues for therapy.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-22-0176
  35. Blood Adv. 2023 Apr 12. pii: bloodadvances.2022009311. [Epub ahead of print]
    Momelotinib Long-Term Safety and Survival in Myelofibrosis: Integrated Analysis of Phase 3 Randomized-Controlled Trials.
    Srdan Verstovsek, Ruben A Mesa, Vikas Gupta, David Lavie, Viviane Dubruille, Nathalie Cambier, Uwe Platzbecker, Marek Hus, Blanca Xicoy, Stephen T Oh, Jean-Jacques Kiladjian, Alessandro M Vannucchi, Aaron T Gerds, Miklos Egyed, Jiri Mayer, Tomasz Sacha, Jun Kawashima, Marc Morris, Mei Huang, Claire N Harrison.
      Momelotinib is the first inhibitor of Janus kinase 1 (JAK1) and JAK2 shown to also inhibit activin A receptor type 1 (ACVR1), a key regulator of iron homeostasis, and has demonstrated improvements in splenomegaly, constitutional symptoms, and anemia in myelofibrosis. This long-term analysis pooled data from 3 randomized phase 3 studies of momelotinib (MOMENTUM, SIMPLIFY-1, SIMPLIFY-2), representing myelofibrosis disease from early (JAK inhibitor-naive) to late (JAK inhibitor-experienced) stages. Patients in the control arms (danazol in MOMENTUM; ruxolitinib in SIMPLIFY-1; best available therapy in SIMPLIFY-2) could cross over to receive momelotinib at the end of the 24-week randomized period, and all patients could continue momelotinib treatment after the completion of these studies via an extended access protocol. Across these studies, 725 patients with myelofibrosis received momelotinib; 12% remained on therapy for ≥5 years, with a median treatment exposure of 11.3 months (range, 0.1-90.4 months). The most common nonhematologic treatment-emergent adverse event (AE) occurring in ≥20% of patients was diarrhea (any grade, 27%; grade ≥3, 3%). Any-grade thrombocytopenia, anemia, and neutropenia occurred in 25%, 23%, and 7% of patients, respectively. The most common reason for momelotinib discontinuation was thrombocytopenia (4% rate of discontinuation). Incidence of AEs of clinical importance (eg, infections, malignant transformation, peripheral neuropathy, hemorrhage) did not increase over time. This analysis of one of the largest randomized trial databases for a JAK inhibitor to date in myelofibrosis demonstrated a consistent safety profile of momelotinib without long-term or cumulative toxicity.
    DOI:  https://doi.org/10.1182/bloodadvances.2022009311
  36. Nat Commun. 2023 Apr 14. 14(1): 2155
    Oncogenic drivers dictate immune control of acute myeloid leukemia.
    Rebecca J Austin, Jasmin Straube, Rohit Halder, Yashaswini Janardhanan, Claudia Bruedigam, Matthew Witkowski, Leanne Cooper, Amy Porter, Matthias Braun, Fernando Souza-Fonseca-Guimaraes, Simone A Minnie, Emily Cooper, Sebastien Jacquelin, Axia Song, Tobias Bald, Kyohei Nakamura, Geoffrey R Hill, Iannis Aifantis, Steven W Lane, Megan J Bywater.
      Acute myeloid leukemia (AML) is a genetically heterogeneous, aggressive hematological malignancy induced by distinct oncogenic driver mutations. The effect of specific AML oncogenes on immune activation or suppression is unclear. Here, we examine immune responses in genetically distinct models of AML and demonstrate that specific AML oncogenes dictate immunogenicity, the quality of immune response and immune escape through immunoediting. Specifically, expression of NrasG12D alone is sufficient to drive a potent anti-leukemia response through increased MHC Class II expression that can be overcome with increased expression of Myc. These data have important implications for the design and implementation of personalized immunotherapies for patients with AML.
    DOI:  https://doi.org/10.1038/s41467-023-37592-9
  37. Leuk Lymphoma. 2023 Apr 13. 1-6
    Real-world outcomes of frontline venetoclax-based therapy in older adults with acute myeloid leukemia: an analysis utilizing EHR data.
    Fieke W Hoff, Prapti A Patel, Andrew J Belli, Eric Hansen, Heidi Foss, Molly Schulte, Ching-Kun Wang, Yazan F Madanat.
      Venetoclax (VEN) in combination with hypomethylating agents (HMA) or low-dose cytarabine has become the standard of care for patients with acute myeloid leukemia (AML) who are ineligible to receive intensive induction chemotherapy. Clinical trials are performed in a controlled setting that can be difficult to emulate in the real world. We sought to investigate outcomes of patients treated with VEN-based therapy in the real world. Patients with an age of ≥65 years who received frontline VEN-based therapy were identified using the COTA database (n = 112). The majority of patients (91%) were treated in the community setting and had adverse-risk AML (63%). The real-world overall response rate (rwORR) was 55% with a median real-world overall survival (rwOS) of 13 months after VEN/HMA. The rwORR was lower and median rwOS was shorter than those reported in the VIALE-A trial, underscoring the importance of studying novel therapies using real-world data.
    Keywords:  AML; Real-world; VIALE-A; venetoclax
    DOI:  https://doi.org/10.1080/10428194.2023.2197090
  38. JCI Insight. 2023 Apr 13. pii: e167744. [Epub ahead of print]
    Multi-omics of Bohring-Opitz syndrome truncating ASXL1 mutations identify canonical and non-canonical Wnt signaling dysregulation.
    Isabella Lin, Angela Wei, Zain Awamleh, Meghna Singh, Aileen Ning, Analeyla Herrera, Bianca E Russell, Rosanna Weksberg, Valerie A Arboleda.
      ASXL1 (Additional sex combs-like 1) plays key roles in epigenetic regulation of early developmental gene expression. De novo truncating mutations in ASXL1 cause Bohring-Opitz syndrome (BOS, OMIM #605039), a rare neurodevelopmental condition characterized by severe intellectual disabilities, characteristic facial features, hypertrichosis, increased risk of Wilms tumor, and variable congenital anomalies including heart defects and severe skeletal defects giving rise to a typical 'BOS posture'. These BOS-causing ASXL1 variants are also high-prevalence somatic driver mutations in acute myeloid leukemia (AML). We use primary cells from BOS individuals (n = 18) and controls (n = 49) to dissect gene regulatory changes caused by ASXL1 mutations using comprehensive multi-omics assays for chromatin accessibility (ATAC-seq), DNA methylation, histone methylation binding, and transcriptome in peripheral blood and skin fibroblasts. Our data shows that regardless of cell type, ASXL1 mutations drive strong cross-tissue effects that disrupt multiple layers of the epigenome. The data showed a broad activation of canonical Wnt signaling at the transcriptional and protein levels and upregulation of VANGL2, a planar cell polarity pathway protein that acts through non-canonical Wnt signaling to direct tissue patterning and cell migration. This multi-omics approach identifies the core impact of ASXL1 mutations and therapeutic targets for BOS and myeloid leukemias.
    Keywords:  Development; Epigenetics; Genetic diseases; Genetics; Leukemias
    DOI:  https://doi.org/10.1172/jci.insight.167744
  39. Cancers (Basel). 2023 Mar 27. pii: 1988. [Epub ahead of print]15(7):
    High Throughput Fluorescence-Based In Vitro Experimental Platform for the Identification of Effective Therapies to Overcome Tumour Microenvironment-Mediated Drug Resistance in AML.
    Yoana Arroyo-Berdugo, Maria Sendino, David Greaves, Natalia Nojszewska, Orest Idilli, Chi Wai So, Lucy Di Silvio, Ruby Quartey-Papafio, Farzin Farzaneh, Jose Antonio Rodriguez, Yolanda Calle.
      The interactions between Acute Myeloid Leukaemia (AML) leukemic stem cells and the bone marrow (BM) microenvironment play a critical role during AML progression and resistance to drug treatments. Therefore, the identification of novel therapies requires drug-screening methods using in vitro co-culture models that closely recreate the cytoprotective BM setting. We have developed a new fluorescence-based in vitro co-culture system scalable to high throughput for measuring the concomitant effect of drugs on AML cells and the cytoprotective BM microenvironment. eGFP-expressing AML cells are co-cultured in direct contact with mCherry-expressing BM stromal cells for the accurate assessment of proliferation, viability, and signaling in both cell types. This model identified several efficacious compounds that overcome BM stroma-mediated drug resistance against daunorubicin, including the chromosome region maintenance 1 (CRM1/XPO1) inhibitor KPT-330. In silico analysis of genes co-expressed with CRM1, combined with in vitro experiments using our new methodology, also indicates that the combination of KPT-330 with the AURKA pharmacological inhibitor alisertib circumvents the cytoprotection of AML cells mediated by the BM stroma. This new experimental model and analysis provide a more precise screening method for developing improved therapeutics targeting AML cells within the cytoprotective BM microenvironment.
    Keywords:  AML; KPT-330; co-culture system; daunorubicin; resistance; selinexor; tumour microenvironment
    DOI:  https://doi.org/10.3390/cancers15071988
  40. Br J Haematol. 2023 Apr 10.
    New insights into the clinical characteristics of SETD2-mutated acute myeloid leukaemia.
    Xiang Zhang, Ziwei Wang, Jiewen Sun, Lixia Liu, Jiayue Qin, Aijie Huang, Min Yang, Yinjun Lou, Gusheng Tang, Liping Mao, Jiejin Qian, Juying Wei, Wenyuan Mai, Haitao Meng, Jianmin Yang, Hongyan Tong, Jianmin Wang, Wenjuan Yu, Xiong Ni, Jie Jin.
      As reported, SETD2 is recurrently mutated in acute myeloid leukaemia (AML), but knowledge about the specifics is limited. We enrolled 530 consecutive newly diagnosed AML patients in our study, and we analysed the distribution pattern and prognostic role of SETD2 mutation in AML. SETD2 mutation was found to affect 6.3% of AML patients, and it frequently co-occurred with IDH2, NRAS and CEBPA mutations. SETD2-mutated patients saw excellent therapeutic responses but failed to gain better survival time than other patients. This could be because of the high recurrence and mortality in SETD2-mutated patients who have additional mutations, such as NRAS mutation.
    Keywords:  SETD2 mutation; acute myeloid leukaemia; distribution pattern; prognosis
    DOI:  https://doi.org/10.1111/bjh.18811
  41. Blood. 2023 Apr 13. 141(15): 1784-1785
    Gold is gold even in mud: NPM1 mutations in T-AML.
    Celalettin Ustun.
      
    DOI:  https://doi.org/10.1182/blood.2022019295
  42. Cell Rep. 2023 Apr 13. pii: S2211-1247(23)00384-4. [Epub ahead of print]42(4): 112373
    Elevated enhancer-oncogene contacts and higher oncogene expression levels by recurrent CTCF inactivating mutations in acute T cell leukemia.
    Willem K Smits, Carlo Vermeulen, Rico Hagelaar, Shunsuke Kimura, Eric M Vroegindeweij, Jessica G C A M Buijs-Gladdines, Ellen van de Geer, Marjon J A M Verstegen, Erik Splinter, Simon V van Reijmersdal, Arjan Buijs, Niels Galjart, Winfried van Eyndhoven, Max van Min, Roland Kuiper, Patrick Kemmeren, Charles G Mullighan, Wouter de Laat, Jules P P Meijerink.
      Monoallelic inactivation of CCCTC-binding factor (CTCF) in human cancer drives altered methylated genomic states, altered CTCF occupancy at promoter and enhancer regions, and deregulated global gene expression. In patients with T cell acute lymphoblastic leukemia (T-ALL), we find that acquired monoallelic CTCF-inactivating events drive subtle and local genomic effects in nearly half of t(5; 14) (q35; q32.2) rearranged patients, especially when CTCF-binding sites are preserved in between the BCL11B enhancer and the TLX3 oncogene. These solitary intervening sites insulate TLX3 from the enhancer by inducing competitive looping to multiple binding sites near the TLX3 promoter. Reduced CTCF levels or deletion of the intervening CTCF site abrogates enhancer insulation by weakening competitive looping while favoring TLX3 promoter to BCL11B enhancer looping, which elevates oncogene expression levels and leukemia burden.
    Keywords:  BCL11B; CP: Cancer; CTCF mutation; T cell acute lymphoblastic leukemia; TLX3; competitive chromatin looping; enhancer insulation; oncogene regulation
    DOI:  https://doi.org/10.1016/j.celrep.2023.112373
  43. Blood Cancer J. 2023 04 10. 13(1): 49
    Observation and treatment in DDX41-mutated acute myeloid leukemia and myelodysplastic syndrome.
    Aref Al-Kali, Ahmad Nanaa, David Viswanatha, Rong He, Phuong Nguyen, Dragan Jevremovic, James M Foran, Cecelia Arana Yi, Patricia T Greipp, Naseema Gangat, Mrinal Patnaik, Ayalew Tefferi, Mark R Litzow, Abhishek A Mangaonkar, Mithun Vinod Shah, Talha Badar, Hassan B Alkhateeb.
      
    DOI:  https://doi.org/10.1038/s41408-023-00818-6
  44. Nature. 2023 Apr 12.
    Clonal haematopoiesis and risk of chronic liver disease.
    NHLBI TOPMed Hematology Working Group
      Chronic liver disease is a major public health burden worldwide1. Although different aetiologies and mechanisms of liver injury exist, progression of chronic liver disease follows a common pathway of liver inflammation, injury and fibrosis2. Here we examined the association between clonal haematopoiesis of indeterminate potential (CHIP) and chronic liver disease in 214,563 individuals from 4 independent cohorts with whole-exome sequencing data (Framingham Heart Study, Atherosclerosis Risk in Communities Study, UK Biobank and Mass General Brigham Biobank). CHIP was associated with an increased risk of prevalent and incident chronic liver disease (odds ratio = 2.01, 95% confidence interval (95% CI) [1.46, 2.79]; P < 0.001). Individuals with CHIP were more likely to demonstrate liver inflammation and fibrosis detectable by magnetic resonance imaging compared to those without CHIP (odds ratio = 1.74, 95% CI [1.16, 2.60]; P = 0.007). To assess potential causality, Mendelian randomization analyses showed that genetic predisposition to CHIP was associated with a greater risk of chronic liver disease (odds ratio = 2.37, 95% CI [1.57, 3.6]; P < 0.001). In a dietary model of non-alcoholic steatohepatitis, mice transplanted with Tet2-deficient haematopoietic cells demonstrated more severe liver inflammation and fibrosis. These effects were mediated by the NLRP3 inflammasome and increased levels of expression of downstream inflammatory cytokines in Tet2-deficient macrophages. In summary, clonal haematopoiesis is associated with an elevated risk of liver inflammation and chronic liver disease progression through an aberrant inflammatory response.
    DOI:  https://doi.org/10.1038/s41586-023-05857-4
  45. Am J Hematol. 2023 Apr 13.
    Associations of minor histocompatibility antigens with outcomes following allogeneic hematopoietic cell transplantation.
    Othmane Jadi, Hancong Tang, Kelly Olsen, Steven Vensko, Qianqian Zhu, Yiwen Wang, Christopher A Haiman, Loreall Pooler, Xin Sheng, Guy Brock, Amy Webb, Marcelo C Pasquini, Philip L McCarthy, Stephen R Spellman, Theresa Hahn, Benjamin Vincent, Paul Armistead, Lara E Sucheston-Campbell.
      The role of minor histocompatibility antigens (mHAs) in mediating graft versus leukemia and graft versus host disease (GvHD) following allogeneic hematopoietic cell transplantation (alloHCT) is recognized but not well-characterized. By implementing improved methods for mHA prediction in two large patient cohorts, this study aimed to comprehensively explore the role of mHAs in alloHCT by analyzing whether (1) the number of predicted mHAs, or (2) individual mHAs are associated with clinical outcomes. The study population consisted of 2249 donor-recipient pairs treated for acute myeloid leukemia and myelodysplastic syndrome with alloHCT. A Cox proportional hazard model showed that patients with a class I mHA count greater than the population median had an increased hazard of GvHD mortality (hazard ratio [HR] = 1.39, 95% confidence interval [CI] = 1.01, 1.77, p = .046). Competing risk analyses identified the class I mHAs DLRCKYISL (GSTP), WEHGPTSLL (CRISPLD2), and STSPTTNVL (SERPINF2) were associated with increased GVHD mortality (HR = 2.84, 95% CI = 1.52, 5.31, p = .01), decreased leukemia-free survival (LFS) (HR = 1.94, 95% CI = 1.27, 2.95, p = .044), and increased disease-related mortality (DRM) (HR = 2.32, 95% CI = 1.5, 3.6, p = .008), respectively. One class II mHA YQEIAAIPSAGRERQ (TACC2) was associated with increased risk of treatment-related mortality (TRM) (HR = 3.05, 95% CI = 1.75, 5.31, p = .02). WEHGPTSLL and STSPTTNVL were both present within HLA haplotype B*40:01-C*03:04 and showed a positive dose-response relationship with increased all-cause mortality and DRM and decreased LFS, indicating these two mHAs contribute to the risk of mortality in an additive manner. Our study reports the first large-scale investigation of the associations of predicted mHA peptides with clinical outcomes following alloHCT.
    DOI:  https://doi.org/10.1002/ajh.26925
  46. Clin Cancer Res. 2023 Apr 10. pii: CCR-22-3192. [Epub ahead of print]
    PI3K Inhibition Restores and Amplifies Response to Ruxolitinib in patients with Myelofibrosis.
    Tamara K Moyo, Ashwin Kishtagari, Matthew Villaume, Brandon McMahon, Sanjay R Mohan, Tess Stopczynski, Sheau-Chiann Chen, Run Fan, Yuankai Huo, Hyeonsoo Moon, Yucheng Tang, Cosmin A Bejan, Merrida Childress, Ingrid Anderson, Kyle Rawling, Rhea M Simons, Ashley Moncrief, Rebekah Caza, Laura Dugger, Aunshka Collins, Channing V Dudley, P Brent Ferrell, Michael Byrne, Stephen A Strickland, Gregory D Ayers, Bennett A Landman, Emily F Mason, Ruben A Mesa, Jeanne M Palmer, Laura C Michaelis, Michael R Savona.
       PURPOSE: Treatment options are limited beyond JAK inhibitors for patients with primary myelofibrosis (PMF), or secondary MF. Preclinical studies have revealed that PI3Kδ inhibition cooperates with ruxolitinib, a JAK1/2 inhibitor, to reduce proliferation and induce apoptosis of JAK2V617F mutant cell lines.
    PATIENTS AND METHODS: In a phase I dose-escalation and expansion study, we evaluated the safety and efficacy of a selective PI3Kδ inhibitor umbralisib in combination with ruxolitinib in MF patients who had a suboptimal response or lost response to ruxolitinib. Enrolled subjects were required to be on a stable dose of ruxolitinib for ≥8 weeks and continue that maximally tolerated dose at study enrollment. The recommended dose of umbralisib in combination with ruxolitinib was determined using a modified 3+3 dose escalation design. Safety, pharmacokinetics, and efficacy outcomes were evaluated, and spleen size was measured with a novel automated digital atlas.
    RESULTS: Thirty-seven MF patients with prior exposure to ruxolitinib were enrolled. 2 patients treated with 800mg umbralisib experienced reversible Grade 3 asymptomatic pancreatic enzyme elevation, but no dose-limiting toxicities were seen at lower umbralisib doses. Two patients (5%) achieved complete response (CR), and 12 patients (32%) met the IWG-MRT response criteria of clinical improvement (CI). With a median follow-up of 50.3 months for censored patients, overall survival was greater than 70% after 3 years of follow-up.
    CONCLUSIONS: Adding umbralisib to ruxolitinib in patients was well-tolerated and may re-sensitize MF patients to ruxolitinib without unacceptable rates of adverse events seen with earlier generation PI3Kδ inhibitors.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-3192
  47. Front Oncol. 2023 ;13 1137175
    Venetoclax plus hypomethylating agents versus intensive chemotherapy for hematological relapse of myeloid malignancies after allo-HSCT.
    Zhangjie Chen, Sisi Zhen, Tingting Zhang, Yuyan Shen, Aiming Pang, Donglin Yang, Rongli Zhang, Qiaoling Ma, Yi He, Jialin Wei, Weihua Zhai, Xin Chen, Erlie Jiang, Mingzhe Han, Sizhou Feng.
       Introduction: Since allogeneic stem cell transplantation (allo-HSCT) is considered one of the curative treatments for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), hematological relapse following allo-HSCT remained a crucial concern for patients' survival.
    Methods: We retrospectively compared patients who received venetoclax plus hypomethylating agents (VEN+HMA, n=23) or intensive chemotherapy (IC, n=42) for hematological relapse of myeloid malignancies after allo-HSCT. HMA selection included decitabine (n=2) and azacitidine (n=21), and combined donor lymphocyte infusion was administered to 21 and 42 patients in VEN+HMA and IC groups, respectively.
    Results: Median age of all patients was 39 (16-64) years old. Overall response rates, including complete response (CR), CR with incomplete recovery of normal neutrophil or platelet counts (CRi) and partial response (PR), were not significantly different between VEN+HMA and IC groups (60.1% versus 64.3%, P=0.785). CR/CRi rate was 52.2% in VEN+HMA and 59.5% in IC group (P=0.567). The rate of relapse after response was 66.7% in VEN+HMA group and 40.7% in IC group (P=0.176). Median overall survival was 209.0 (95%CI 130.9-287.1) days for VEN+HMA group versus 211.0 (95%CI 28.7-393.3) days for IC group (P=0.491). The incidence of lung infection (17.4% versus 50.0%, P=0.010), thrombocytopenia (73.9% versus 95.2%, P=0.035) and acute graft-versus-host disease (aGvHD) (50.0% versus 13.0%, P=0.003) was significantly higher in IC group.
    Discussion: In conclusion, VEN+HMA is not inferior to IC regimen in terms of improving response and survival, and is associated with a lower incidence of adverse events and aGvHD. However, further research is required to enhance long-term survival.
    Keywords:  acute myeloid leukemia; allo-HSCT; myeloid malignancy; relapse; venetoclax
    DOI:  https://doi.org/10.3389/fonc.2023.1137175
  48. medRxiv. 2023 Mar 29. pii: 2023.03.24.23287521. [Epub ahead of print]
    Phase II Study of Myeloablative 8/8- or 7/8-Matched Allotransplantation with Post-Transplant Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil: Marked Reduction in GVHD Risk Without Increased Relapse Risk Compared to Historical Cyclosporine/Methotrexate.
    Najla El Jurdi, Alex Hoover, Daniel O'Leary, Qing Cao, Ashish Gupta, Christen Ebens, Joseph Maakaron, Brian C Betts, Armin Rashidi, Mark Juckett, Troy Lund, Veronika Bachanova, Margaret MacMillan, Jeffrey Miller, Paul Orchard, John Wagner, Gregory Vercellotti, Daniel Weisdorf, Kathryn Dusenbery, Stephanie Terezakis, Shernan Holtan.
       Introduction: Graft-versus host disease (GVHD) is a major limitation to the success of allogeneic hematopoietic cell transplant (HCT). We hypothesized that the GVHD prophylaxis regimen of post-transplant cyclophosphamide (PTCy), tacrolimus (Tac) and mycophenolate mofetil (MMF) would reduce the incidence of GVHD in patients receiving a matched or single antigen mismatched HCT without an increase in risk of malignant relapse.
    Methods: This is a phase II study conducted at the University of Minnesota using a myeloablative regimen of either: (A) total body irradiation (TBI, total dose 1320 cGy, administered in 165 cGy fractions, twice a day from days -4 to -1) or (B) Busulfan 3.2mg/kg daily (cumulative AUC 19,000 - 21,000 μmol/min/L) plus fludarabine 160mg/m 2 days -5 to -2, followed by a GVHD prophylaxis regimen of PTCy (50mg/kg days +3 and +4), Tac and MMF (beginning day +5). The primary endpoint is cumulative incidence of chronic GVHD requiring systemic immunosuppression at 1-year post-transplant. We compared results to our previous myeloablative protocol for matched donors utilizing cyclosporine/methotrexate (CSA/MTX) GVHD prophylaxis.
    Results: From March 2018 - June 2022, we enrolled and treated 125 pediatric and adult patients with a median follow up of 472 days. Grade II-IV acute GVHD occurred in 16% (95% confidence interval (CI): 9-23%); Grade III-IV acute GVHD was 4% (CI: 0-8%). No patients experienced grade IV GVHD, and there were no deaths due to GVHD before day 100. Only 3 developed chronic GVHD requiring immune suppression, (4%, CI: 0-8%). Two-year overall survival (OS) was 80% (CI: 69-87%), and (graft-versus-host disease-free, relapse-free survival) GRFS 57% (CI: 45-67%), both higher than historical CSA/MTX. The incidence of grade II-IV aGVHD, cGVHD, and NRM were all lower with PTCy/Tac/MMF compared to historical CSA/MTX. One-quarter (25%) experienced relapse (CI: 15-36%) similar to historical CSA/MTX. There was no statistically significant difference in survival outcomes between recipients of matched versus 7/8 donors.
    Conclusion: Myeloablative HCT with PTCy/Tac/MMF results in extremely low incidence of severe acute or chronic GVHD, the primary endpoint of this clinical trial. Relapse risk is not increased compared to our historical CSA/MTX cohort.
    DOI:  https://doi.org/10.1101/2023.03.24.23287521
  49. Cell. 2023 Apr 05. pii: S0092-8674(23)00275-1. [Epub ahead of print]
    Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease.
    Zixi Wang, Shijia Zhu, Yuemeng Jia, Yunguan Wang, Naoto Kubota, Naoto Fujiwara, Ruth Gordillo, Cheryl Lewis, Min Zhu, Tripti Sharma, Lin Li, Qiyu Zeng, Yu-Hsuan Lin, Meng-Hsiung Hsieh, Purva Gopal, Tao Wang, Matt Hoare, Peter Campbell, Yujin Hoshida, Hao Zhu.
      Somatic mutations in nonmalignant tissues accumulate with age and injury, but whether these mutations are adaptive on the cellular or organismal levels is unclear. To interrogate genes in human metabolic disease, we performed lineage tracing in mice harboring somatic mosaicism subjected to nonalcoholic steatohepatitis (NASH). Proof-of-concept studies with mosaic loss of Mboat7, a membrane lipid acyltransferase, showed that increased steatosis accelerated clonal disappearance. Next, we induced pooled mosaicism in 63 known NASH genes, allowing us to trace mutant clones side by side. This in vivo tracing platform, which we coined MOSAICS, selected for mutations that ameliorate lipotoxicity, including mutant genes identified in human NASH. To prioritize new genes, additional screening of 472 candidates identified 23 somatic perturbations that promoted clonal expansion. In validation studies, liver-wide deletion of Tbx3, Bcl6, or Smyd2 resulted in protection against hepatic steatosis. Selection for clonal fitness in mouse and human livers identifies pathways that regulate metabolic disease.
    Keywords:  Gpam; Mboat7; NAFLD; NASH; Smyd2; Tbx3; chronic liver disease; fatty liver disease; in vivo screening; somatic mosaicism
    DOI:  https://doi.org/10.1016/j.cell.2023.03.014
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