bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2023‒05‒07
35 papers selected by
Paolo Gallipoli
Barts Cancer Institute, Queen Mary University of London
  1. Interaction between myelodysplasia-related gene mutations and ontogeny in acute myeloid leukemia.
  2. Acute myeloid leukemia stratifies as two clinically relevant sphingolipidomic subtypes.
  3. Evolutionary landscape of clonal hematopoiesis in 3,359 individuals from the general population.
  4. AML classification in the year 2023: How to avoid a Babylonian confusion of languages.
  5. The clinical and molecular spectrum of ETV6 mutated myeloid neoplasms.
  6. Survival improvement of patients with FLT3 mutated acute myeloid leukemia: results from a prospective 9 years cohort.
  7. A non-canonical enzymatic function of PIWIL4 maintains genomic integrity and leukemic growth in AML.
  8. Clinical characteristics and overall survival among acute myeloid leukemia patients with TP53 gene mutation or chromosome 17p deletion.
  9. Total body irradiation versus busulfan based intermediate intensity conditioning for stem cell transplantation in ALL patients >45 years-a registry-based study by the Acute Leukemia Working Party of the EBMT.
  10. Ruxolitinib Versus Best Available Therapy for Polycythemia Vera Intolerant or Resistant to Hydroxycarbamide in a Randomized Trial.
  11. Health-Related Quality of Life and Vulnerability among People with Myelodysplastic Syndromes: A US National Study.
  12. Assessment and validation of the molecular international prognostic scoring system for myelodysplastic syndromes.
  13. Venetoclax Combined with Azacitidine and Homoharringtonine in Relapsed/Refractory AML: A Multicenter, Phase 2 Trial.
  14. An African-specific variant of TP53 reveals PADI4 as a regulator of p53-mediated tumor suppression.
  15. Switching from imatinib to nilotinib plus pegylated interferon-α2b in chronic phase CML failing to achieve deep molecular response: clinical and immunological effects.
  16. Oral Azacitidine for Maintenance Treatment of Acute Myeloid Leukaemia After Induction Therapy: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.
  17. Massively parallel base editing to map variant effects in human hematopoiesis.
  18. Molecular-defined clonal evolution in patients with classical myeloproliferative neoplasms.
  19. Maintenance therapy in acute myeloid leukemia: advances and controversies.
  20. Glucose partitioning in the bone marrow micro-environment in acute myeloid leukaemia.
  21. Germline loss of function BRCA1 and BRCA2 mutations and risk of de novo hematopoietic malignancies.
  22. NUP98::Nsd1 and FLT3-ITD collaborate to generate acute myeloid leukemia.
  23. Telomere Length and Clonal Hematopoiesis.
  24. GTAC enables parallel genotyping of multiple genomic loci with chromatin accessibility profiling in single cells.
  25. BCOR/BCORL1 mutated hypergranular cells mimicking acute promyelocytic leukemia.
  26. Transcription factor induction of vascular blood stem cell niches in vivo.
  27. Tumor-derived interleukin-1α and leukemia inhibitory factor promote extramedullary hematopoiesis.
  28. Inter-organelle cross-talk supports acetyl-coenzyme A homeostasis and lipogenesis under metabolic stress.
  29. Acetyl-CoA biosynthesis drives resistance to histone acetyltransferase inhibition.
  30. High-throughput Approaches to Uncover Synergistic Drug Combinations in Leukemia.
  31. NFIA-ETO2, TP53, and erythroid leukemogenesis.
  32. Cytoplasmic Localization of Mdm2 in Cells Expressing Mutated NPM is Mediated by p53.
  33. Ponatinib, asciminib and inotuzumab ozogamicin: A novel drug combination in acute lymphoblastic leukemia.
  34. Familial Clonal Hematopoiesis in a Long Telomere Syndrome.
  35. Imatinib compared with second-generation tyrosine kinase-inhibitors in persons with chronic myeloid leukemia presenting in accelerated phase.
  1. Blood Adv. 2023 May 04. pii: bloodadvances.2023009675. [Epub ahead of print]
    Interaction between myelodysplasia-related gene mutations and ontogeny in acute myeloid leukemia.
    Joseph G W McCarter, David Nemirovsky, Christopher A Famulare, Noushin Farnoud, Abhinita S Mohanty, Zoe S Stone-Molloy, Jordan Chervin, Brian J Ball, Zachary D Epstein-Peterson, Maria E Arcila, Aaron J Stonestrom, Andrew Dunbar, Sheng F Cai, Jacob L Glass, Mark B Geyer, Raajit K Rampal, Ellin Berman, Omar I Abdel-Wahab, Eytan M Stein, Martin S Tallman, Ross L Levine, Aaron D Goldberg, Elli Papaemmanuil, Yanming Zhang, Mikhail Roshal, Andriy Derkach, Wenbin Xiao.
      Accurate classification and risk stratification is critical for clinical decision making in AML patients. In the newly proposed World Health Organization (WHO) and International Consensus classifications (ICC) of hematolymphoid neoplasms, the presence of myelodysplasia-related (MR) gene mutations is included as one of the diagnostic criteria of AML, myelodysplasia-related (AML-MR), largely based on the assumption that these mutations are specific for AML with an antecedent myelodysplastic syndrome. ICC also prioritizes MR gene mutations over ontogeny (as defined by clinical history). Furthermore, European LeukemiaNet (ELN) 2022 stratifies these MR gene mutations to the adverse-risk group. By thoroughly annotating a cohort of 344 newly diagnosed AML patients treated at Memorial Sloan Kettering Cancer Center (MSKCC), we show that ontogeny assignment based on database registry lacks accuracy. MR gene mutations are frequently seen in de novo AML. Among MR gene mutations, only EZH2 and SF3B1 were associated with an inferior outcome in a univariate analysis. In a multivariate analysis, AML ontogeny had independent prognostic values even after adjusting for age, treatment, allo-transplant and genomic classes or ELN risks. Ontogeny also stratified the outcome of AML with MR gene mutations. Finally, de novo AML with MR gene mutations did not show an adverse outcome. In summary, our study emphasizes the importance of accurate ontogeny designation in clinical studies, demonstrates the independent prognostic value of AML ontogeny and questions the current classification and risk stratification of AML with MR gene mutations.
    DOI:  https://doi.org/10.1182/bloodadvances.2023009675
  2. bioRxiv. 2023 Apr 17. pii: 2023.04.13.536805. [Epub ahead of print]
    Acute myeloid leukemia stratifies as two clinically relevant sphingolipidomic subtypes.
    B Bishal Paudel, Su-Fern Tan, Todd E Fox, Johnson Ung, Jeremy Shaw, Wendy Dunton, Irene Lee, Arati Sharma, Aaron D Viny, Brian M Barth, Martin S Tallman, Myles Cabot, Francine E Garrett-Bakelman, Ross L Levine, Mark Kester, David Claxton, David J Feith, Kevin A Janes, Thomas P Loughran.
      Acute myeloid leukemia (AML) is an aggressive disease with complex and heterogeneous biology. Although several genomic classifications have been proposed, there is a growing interest in going beyond genomics to stratify AML. In this study, we profile the sphingolipid family of bioactive molecules in 213 primary AML samples and 30 common human AML cell lines. Using an integrative approach, we identify two distinct sphingolipid subtypes in AML characterized by a reciprocal abundance of hexosylceramide (Hex) and sphingomyelin (SM) species. The two Hex-SM clusters organize diverse samples more robustly than known AML driver mutations and are coupled to latent transcriptional states. Using transcriptomic data, we develop a machine-learning classifier to infer the Hex-SM status of AML cases in TCGA and BeatAML clinical repositories. The analyses show that the sphingolipid subtype with deficient Hex and abundant SM is enriched for leukemic stemness transcriptional programs and comprises an unappreciated high-risk subgroup with poor clinical outcomes. Our sphingolipid-focused examination of AML identifies patients least likely to benefit from standard of care and raises the possibility that sphingolipidomic interventions could switch the subtype of AML patients who otherwise lack targetable alternatives.Key Points: 1.Sphingolipidomics separates acute myeloid leukemia (AML) patients and cell lines into two subtypes.2.The subtype with low hexosylceramide and high sphingomyelin defines a new high-risk subtype with poor clinical outcomes.
    DOI:  https://doi.org/10.1101/2023.04.13.536805
  3. Cancer Cell. 2023 May 03. pii: S1535-6108(23)00132-0. [Epub ahead of print]
    Evolutionary landscape of clonal hematopoiesis in 3,359 individuals from the general population.
    Isabelle A van Zeventer, Aniek O de Graaf, Jonas B Salzbrunn, Ilja M Nolte, Priscilla Kamphuis, Avinash Dinmohamed, Bert A van der Reijden, Jan Jacob Schuringa, Joop H Jansen, Gerwin Huls.
      Knowledge about evolution of clonal hematopoiesis, which may drive malignant progression, is crucial for clinical decision-making. We investigated the landscape of clonal evolution by error-corrected sequencing on 7,045 sequential samples from 3,359 individuals in the prospective population-based Lifelines cohort, with a special focus on cytosis and cytopenia. Spliceosome (SRSF2/U2AF1/SF3B1) and JAK2 mutated clones show highest growth rates over a median 3.6-year period, while clone sizes for DNMT3A and TP53 increase only marginally, independent of cytosis or cytopenia. Nevertheless, large differences are observed between individuals carrying the same mutation, indicative of modulation by non-mutation-related factors. Clonal expansion is not dependent on classical cancer risk factors (e.g., smoking). Risk for incident myeloid malignancy diagnosis is highest for JAK2, spliceosome, or TP53 mutations and absent for DNMT3A, and it is mostly preceded by cytosis or cytopenia. The results provide important insight into high-risk evolutionary patterns to guide monitoring of "CHIP" and "CCUS."
    Keywords:  CHIP; Cytopenia; clonal evolution; clonal hematopoiesis; cytosis; elderly; somatic mutations
    DOI:  https://doi.org/10.1016/j.ccell.2023.04.006
  4. Leukemia. 2023 Apr 29.
    AML classification in the year 2023: How to avoid a Babylonian confusion of languages.
    Sandra Huber, Constance Baer, Stephan Hutter, Frank Dicker, Manja Meggendorfer, Christian Pohlkamp, Wolfgang Kern, Torsten Haferlach, Claudia Haferlach, Gregor Hoermann.
      In parallel to the 5th edition of the World Health Organization Classification of Haematolymphoid Tumours (WHO 2022), an alternative International Consensus Classification (ICC) has been proposed. To evaluate the impact of the new classifications on AML diagnoses and ELN-based risk classification, we analyzed 717 MDS and 734 AML non-therapy-related patients diagnosed according to the revised 4th WHO edition (WHO 2017) by whole genome and transcriptome sequencing. In both new classifications, the purely morphologically defined AML entities decreased from 13% to 5%. Myelodysplasia-related (MR) AML increased from 22% to 28% (WHO 2022) and 26% (ICC). Other genetically-defined AML remained the largest group, and the abandoned AML-RUNX1 was mainly reclassified as AML-MR (WHO 2022: 77%; ICC: 96%). Different inclusion criteria of AML-CEBPA and AML-MR (i.a. exclusion of TP53 mutated cases according to ICC) were associated with differences in overall survival. In conclusion, both classifications focus on more genetics-based definitions with similar basic concepts and a large degree of agreement. The remaining non-comparability (e.g., TP53 mutated AML) needs additional studies to definitely answer open questions on disease categorization in an unbiased way.
    DOI:  https://doi.org/10.1038/s41375-023-01909-w
  5. Br J Haematol. 2023 May 05.
    The clinical and molecular spectrum of ETV6 mutated myeloid neoplasms.
    Mark Gurney, Ismahene Chekkaf, Anmol Baranwal, Rami Basmaci, Bahga Katamesh, Patricia Greipp, James M Foran, Talha Badar, Abhishek A Mangaonkar, Kebede H Begna, Naseema Gangat, Mrinal M Patnaik, Mark R Litzow, Mithun V Shah, David S Viswanatha, Rong He, Hassan B Alkhateeb, Aref Al-Kali.
      ETV6 mutations are rare but recurrent somatic events in myeloid neoplasms and are negatively prognostic in myelodysplastic syndrome. We set out to examine the clinical and molecular characteristics of patients undergoing investigation for myeloid neoplasms, found to have deleterious ETV6 mutations. ETV6 mutations occurred in 33 of 5793 (0.6%) cases investigated and predominantly in high-risk disease entities including MDS with increased blasts, primary myelofibrosis and AML, myelodysplasia-related. In three cases, isolated iso (17q) karyotype was concurrently detected, an otherwise rare karyotype in myeloid neoplasms. ETV6 mutations were frequently subclonal and never occurred as an isolated abnormality with ASXL1 (n = 22, 75%), SRSF2 (n = 14, 42%) and SETBP1 (n = 11, 33%) the predominant co-mutations. Restricting to patients with MDS, higher rates of ASXL1, SETBP1, RUNX1 and U2AF1 mutations occurred in ETV6 mutated cases, relative to a consecutive control cohort with wild-type ETV6. The median OS of the cohort was 17.5 months. This report highlights the clinical and molecular associations of somatic ETV6 mutations in myeloid neoplasms, suggests their occurrence as a later event, and proposes further translational research questions for their role in myeloid neoplasia.
    Keywords:  ETV6; NGS; myelodysplastic syndrome; myeloid neoplasia; transcription factor
    DOI:  https://doi.org/10.1111/bjh.18850
  6. Blood Cancer J. 2023 May 05. 13(1): 69
    Survival improvement of patients with FLT3 mutated acute myeloid leukemia: results from a prospective 9 years cohort.
    Spanish Cooperative Group for the Study and Treatment of Acute Leukemias and Myelodysplasias (CETLAM)
      Midostaurin added to intensive chemotherapy is the standard of care for acute myeloid leukemia (AML) with FLT3 mutations (FLT3mut). We analyzed the impact of midostaurin in 227 FLT3mut-AML patients included in the AML-12 prospective trial for fit patients ≤70 years (#NCT04687098). Patients were divided into an early (2012-2015) and late (2016-2020) cohorts. They were uniformly treated except for the addition of midostaurin in 71% of late group patients. No differences were observed in response rates or the number of allotransplants between groups. Outcome was improved in the late period: 2-year relapse incidence decreased from 42% vs 29% in early vs late group (p = 0.024) and 2-year overall survival (OS) improved from 47% vs 61% (p = 0.042), respectively. The effect of midostaurin was evident in NPM1mut patients (n = 151), with 2-yr OS of 72% (exposed) vs 50% (naive) patients (p = 0.011) and mitigated FLT3-ITD allelic ratio prognostic value: 2-yr OS with midostaurin was 85% and 58% in low and high ratio patients (p = 0.049) vs 67% and 39% in naive patients (p = 0.005). In the wild-type NPM1 subset (n = 75), we did not observe significant differences between both study periods. In conclusion, this study highlights the improved outcome of FLT3mut AML fit patients with the incorporation of midostaurin.
    DOI:  https://doi.org/10.1038/s41408-023-00839-1
  7. Blood. 2023 May 05. pii: blood.2022018651. [Epub ahead of print]
    A non-canonical enzymatic function of PIWIL4 maintains genomic integrity and leukemic growth in AML.
    Shiva Bamezai, Alex Jose Pulikkottil, Tribhuwan Yadav, Vegi Mahalakshmi Naidu, Julia Mueller, Jasmin Mark, Tamoghna Mandal, Kristin Anja Feder, Susann Lehle, Chenlin Song, Reinhild Rosler, Sebastian Wiese, Jessica I Hoell, Andreas Kloetgen, Aly Karsan, Ankita Kumari, Luke Wojenski, Amit U Sinha, Irene Gonzalez-Menendez, Leticia Quintanilla-Martinez, Elisa Donato, Andreas Trumpp, Elisabeth Kruse, Stephan Hamperl, Lee Zou, Vijay P S Rawat, Christian Buske.
      RNA-binding proteins (RBPs) form a large and diverse class of factors many members of which are overexpressed in hematological malignancies. RBPs participate in various processes of mRNA metabolism and prevent harmful DNA:RNA hybrids or R-loops. Here we report that PIWIL4, a germ stem cell-associated RBP belonging to the RNase H-like superfamily, is overexpressed in acute myeloid leukemia patients and is essential for leukemic stem cell function and AML growth, but dispensable for healthy human hematopoietic stem cells. In AML cells, PIWIL4 binds to a small number of known piwi-interacting RNA. It instead largely interacts with mRNA annotated to protein-coding genic regions and enhancers that are enriched for genes associated with cancer and human myeloid progenitor gene signatures. PIWIL4 depletion in AML cells downregulates human myeloid progenitor signature and LSC-associated genes and upregulates DNA damage signalling. We demonstrate that PIWIL4 is an R-loop resolving enzyme that prevents R-loop accumulation on a subset of AML and LSC-associated genes, and maintains their expression. It also prevents DNA damage, replication stress, and activation of the ATR pathway in AML cells. PIWIL4 depletion potentiates sensitivity to pharmacological inhibition of the ATR pathway and creates a pharmacologically actionable dependency in AML cells.
    DOI:  https://doi.org/10.1182/blood.2022018651
  8. Am J Hematol. 2023 May 04.
    Clinical characteristics and overall survival among acute myeloid leukemia patients with TP53 gene mutation or chromosome 17p deletion.
    Naval G Daver, Shahed Iqbal, Julie Huang, Camille Renard, Joyce Lin, Yang Pan, Mellissa Williamson, Giridharan Ramsingh.
      Approximately 5% to 15% of acute myeloid leukemia (AML) patients have TP53 gene mutations (TP53m), which are associated with very poor outcomes. Adults (≥18 years) with a new AML diagnosis were included from a nationwide, de-identified, real-world database. Patients receiving first-line therapy were divided into three cohorts: venetoclax (VEN) + hypomethylating agents (HMAs; Cohort A), intensive chemotherapy (Cohort B), or HMA without VEN (Cohort C). A total of 370 newly diagnosed AML patients with TP53m (n = 124), chromosome 17p deletion (n = 166), or both (n = 80) were included. The median age was 72 years (range, 24-84); most were male (59%) and White (69%). Baseline bone marrow (BM) blasts were ≤30%, 31%-50%, and >50% in 41%, 24%, and 29% of patients in Cohorts A, B, and C, respectively. BM remission (<5% blasts) with first-line therapy was reported in 54% of patients (115/215) overall, and 67% (38/57), 62% (68/110), and 19% (9/48) for respective cohorts (median BM remission duration: 6.3, 6.9, and 5.4 months). Median overall survival (95% CI) was 7.4 months (6.0-8.8) for Cohort A, 9.4 months (7.2-10.4) for Cohort B, and 5.9 months (4.3-7.5) for Cohort C. There were no differences in survival by treatment type after adjusting for the effects of relevant covariates (Cohort A vs. C adjusted hazard ratio [aHR] = 0.9; 95% CI, 0.7-1.3; Cohort A vs. B aHR = 1.0; 95% CI, 0.7-1.5; and Cohort C vs. B aHR = 1.1; 95% CI, 0.8-1.6). Patients with TP53m AML have dismal outcomes with current therapies, demonstrating the high unmet need for improved treatments.
    DOI:  https://doi.org/10.1002/ajh.26941
  9. Bone Marrow Transplant. 2023 May 05.
    Total body irradiation versus busulfan based intermediate intensity conditioning for stem cell transplantation in ALL patients >45 years-a registry-based study by the Acute Leukemia Working Party of the EBMT.
    Klaus Hirschbühl, Myriam Labopin, Emmanuelle Polge, Didier Blaise, Jean Henri Bourhis, Gerard Socié, Edouard Forcade, Ibrahim Yakoub-Agha, Hélène Labussière-Wallet, Wolfgang Bethge, Patrice Chevallier, Sarah Bonnet, Matthias Stelljes, Alexandros Spyridonidis, Zinaida Peric, Eolia Brissot, Bipin Savani, Sebastian Giebel, Christoph Schmid, Fabio Ciceri, Arnon Nagler, Mohamad Mohty.
      Allogeneic hematopoietic cell transplantation is a potentially curative treatment in high-risk acute lymphoblastic leukemia (ALL). Conditioning regimens based on ≥12 Gray total body irradiation (TBI) represent the current standard in patients ≤45 years, whereas elderly patients frequently receive intermediate intensity conditioning (IIC) to reduce toxicity. To evaluate the role of TBI as a backbone of IIC in ALL, a retrospective, registry-based study included patients >45 years transplanted from matched donors in first complete remission, who had received either fludarabine/TBI 8 Gy (FluTBI8, n = 262), or the most popular, irradiation-free alternative fludarabine/busulfan, comprising busulfan 6.4 mg/kg (FluBu6.4, n = 188) or 9.6 mg/kg (FluBu9.6, n = 51). At two years, overall survival (OS) was 68.5%, 57%, and 62.2%, leukemia-free survival (LFS) was 58%, 42.7%, and 45%, relapse incidence (RI) was 27.2%, 40%, and 30.9%, and non-relapse-mortality (NRM) was 23.1%, 20.7%, and 26.8% for patients receiving FluTBI8Gy, FluBu6.4, and FluBu9.6, respectively. In multivariate analysis, the risk of NRM, acute and chronic graft-versus-host disease was not influenced by conditioning. However, RI was higher after FluBu6.4 (hazard ratio [HR] [95% CI]: 1.85 [1.16-2.95]), and LFS was lower after both FluBu6.4 (HR: 1.56 [1.09-2.23]) and FluBu9.6 (HR: 1.63 [1.02-2.58]) as compared to FluTBI8. Although only resulting in a non-significant advantage in OS, this observation indicates a stronger anti-leukemic efficacy of TBI-based intermediate intensity conditioning.
    DOI:  https://doi.org/10.1038/s41409-023-01966-w
  10. J Clin Oncol. 2023 May 01. JCO2201935
    Ruxolitinib Versus Best Available Therapy for Polycythemia Vera Intolerant or Resistant to Hydroxycarbamide in a Randomized Trial.
    Claire N Harrison, Jyoti Nangalia, Rebecca Boucher, Aimee Jackson, Christina Yap, Jennifer O'Sullivan, Sonia Fox, Isaak Ailts, Amylou C Dueck, Holly L Geyer, Ruben A Mesa, William G Dunn, Eugene Nadezhdin, Natalia Curto-Garcia, Anna Green, Bridget Wilkins, Jason Coppell, John Laurie, Mamta Garg, Joanne Ewing, Steven Knapper, Josephine Crowe, Frederick Chen, Ioannis Koutsavlis, Anna Godfrey, Siamak Arami, Mark Drummond, Jennifer Byrne, Fiona Clark, Carolyn Mead-Harvey, Elizabeth Joanna Baxter, Mary Frances McMullin, Adam J Mead.
      PURPOSE: Polycythemia vera (PV) is characterized by JAK/STAT activation, thrombotic/hemorrhagic events, systemic symptoms, and disease transformation. In high-risk PV, ruxolitinib controls blood counts and improves symptoms.PATIENTS AND METHODS: MAJIC-PV is a randomized phase II trial of ruxolitinib versus best available therapy (BAT) in patients resistant/intolerant to hydroxycarbamide (HC-INT/RES). Primary outcome was complete response (CR) within 1 year. Secondary outcomes included duration of response, event-free survival (EFS), symptom, and molecular response.
    RESULTS: One hundred eighty patients were randomly assigned. CR was achieved in 40 (43%) patients on ruxolitinib versus 23 (26%) on BAT (odds ratio, 2.12; 90% CI, 1.25 to 3.60; P = .02). Duration of CR was superior for ruxolitinib (hazard ratio [HR], 0.38; 95% CI, 0.24 to 0.61; P < .001). Symptom responses were better with ruxolitinib and durable. EFS (major thrombosis, hemorrhage, transformation, and death) was superior for patients attaining CR within 1 year (HR, 0.41; 95% CI, 0.21 to 0.78; P = .01); and those on ruxolitinib (HR, 0.58; 95% CI, 0.35 to 0.94; P = .03). Serial analysis of JAK2V617F variant allele fraction revealed molecular response was more frequent with ruxolitinib and was associated with improved outcomes (progression-free survival [PFS] P = .001, EFS P = .001, overall survival P = .01) and clearance of JAK2V617F stem/progenitor cells. ASXL1 mutations predicted for adverse EFS (HR, 3.02; 95% CI, 1.47 to 6.17; P = .003). The safety profile of ruxolitinib was as previously reported.
    CONCLUSION: The MAJIC-PV study demonstrates ruxolitinib treatment benefits HC-INT/RES PV patients with superior CR, and EFS as well as molecular response; importantly also demonstrating for the first time, to our knowledge, that molecular response is linked to EFS, PFS, and OS.
    DOI:  https://doi.org/10.1200/JCO.22.01935
  11. Blood Adv. 2023 May 05. pii: bloodadvances.2022009000. [Epub ahead of print]
    Health-Related Quality of Life and Vulnerability among People with Myelodysplastic Syndromes: A US National Study.
    Gregory A Abel, Donnie Hebert, Cecilia Lee, Dana E Rollison, Nancy Gillis, Rami S Komrokji, James M Foran, Jane Jijun Liu, Tareq Al Baghdadi, H Joachim Deeg, Steven D Gore, Wael Saber, Steffanie H Wilson, Michael Otterstatter, Jason Thompson, Christine Borchert, Eric Padron, Amy DeZern, David Cella, Mikkael A Sekeres.
      Health-related quality of life (HRQoL) and vulnerability are variably affected in patients with myelodysplastic syndromes (MDS) and other cytopenic states; however, the heterogeneous composition of these diseases has limited our understanding of these domains. The NHLBI-sponsored MDS Natural History Study (NCT02775383) is a prospective cohort enrolling patients undergoing diagnostic work up for suspected MDS or MDS/myeloproliferative neoplasms (MPNs) in the setting of cytopenias. Untreated patients undergo bone marrow assessment with central histopathology review for assignment as MDS, MDS/MPN, idiopathic cytopenia of undetermined significance (ICUS), acute myeloid leukemia (AML) with <30% blasts, and "At-Risk." HRQoL data are collected at enrollment including MDS-specific (QUALMS) and general (e.g., PROMIS Fatigue) instruments. Dichotomized vulnerability is assessed with the VES-13. Baseline HRQoL scores from 449 patients with MDS (n=248), MDS/MPN (n=40), AML<30% (n=15), ICUS (n=48), or At-Risk (n=98) were similar among diagnoses. In MDS, HRQoL was worse for vulnerable participants (e.g., mean PROMIS Fatigue of 56.0 vs. 49.5; p<0.001) and those with worse prognosis (e.g., mean EQ-5D-5L of 73.4, 72.7, and 64.1 for low, intermediate, and high-risk disease; p=0.005). In vulnerable MDS participants (n=84), most had difficulty with prolonged physical activity (88%) such as walking a quarter mile (74%). These data suggest that cytopenias leading to MDS evaluation are associated with similar HRQoL-regardless of eventual diagnosis-with worse HRQoL among the vulnerable. Among those with MDS, lower-risk disease was associated with better HRQoL, but the relationship was lost among the vulnerable, showing for the first time that vulnerability trumps disease risk in affecting HRQoL.
    DOI:  https://doi.org/10.1182/bloodadvances.2022009000
  12. Leukemia. 2023 May 05.
    Assessment and validation of the molecular international prognostic scoring system for myelodysplastic syndromes.
    Luis E Aguirre, Najla Al Ali, David A Sallman, Somedeb Ball, Akriti G Jain, Onyee Chan, Sara M Tinsley-Vance, Andrew Kuykendall, Kendra Sweet, Jeffrey E Lancet, Eric Padron, Rami S Komrokji.
      The Molecular International Prognostic Scoring System (IPSS-M) is a novel risk stratification model for myelodysplastic syndromes (MDS) that builds on the IPSS and IPSS-R by incorporating mutational data. The model showed improved prognostic accuracy over the IPSS-R across three endpoints: overall survival (OS), leukemia-free survival (LFS) and leukemic transformation. This study aimed to validate the findings of the original in a large cohort of MDS patients, as well as assess its validity in therapy-related and hypoplastic MDS. We retrospectively reviewed clinical, cytogenetic and molecular data for 2355 MDS patients treated at the Moffitt Cancer Center. Correlative analysis between IPSS-R and mean IPSS-M scores and outcome predictions was performed on LFS, OS and leukemic transformation. Using the IPSS-M, patients were classified as Very Low (4%), Low (24%), Moderate-Low (14%), Moderate-High (11%), High (19%) and Very-High risk (28%). Median OS was 11.7, 7.1, 4.4, 3.1, 2.3, and 1.3 years from VL to VH risk subgroups. Median LFS was 12.3, 6.9, 3.6, 2.2, 1.4, and 0.5 years respectively. For patients with t-MDS and h-MDS the model retained its prognostic accuracy. Generalized use of this tool will likely result in more accurate prognostic assessment and optimize therapeutic decision-making in MDS.
    DOI:  https://doi.org/10.1038/s41375-023-01910-3
  13. J Hematol Oncol. 2023 Apr 29. 16(1): 42
    Venetoclax Combined with Azacitidine and Homoharringtonine in Relapsed/Refractory AML: A Multicenter, Phase 2 Trial.
    Hua Jin, Yu Zhang, Sijian Yu, Xin Du, Na Xu, Ruoyang Shao, Dongjun Lin, Yanqiu Chen, Jie Xiao, Zhiqiang Sun, Lan Deng, Xinquan Liang, Hongyu Zhang, Ziwen Guo, Min Dai, Pengcheng Shi, Fen Huang, Zhiping Fan, Zhao Yin, Li Xuan, Ren Lin, Xuejie Jiang, Guopan Yu, Qifa Liu.
      BACKGROUND: Relapsed or refractory acute myeloid leukemia (R/R AML) has a dismal prognosis. The aim of this study was to investigate the activity and tolerability of venetoclax combined with azacitidine plus homoharringtonine (VAH) regimen for R/R AML.METHODS: This phase 2 trial was done at ten hospitals in China. Eligible patients were R/R AML (aged 18-65 years) with an Eastern Cooperative Oncology Group performance status of 0-2. Patients received venetoclax (100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-14) and azacitidine (75 mg/m2 on days 1-7) and homoharringtonine (1 mg/m2 on days 1-7). The primary endpoint was composite complete remission rate [CRc, complete response (CR) plus complete response with incomplete blood count recovery (CRi)] after 2 cycles of treatment. The secondary endpoints include safety and survival.
    RESULTS: Between May 27, 2020, and June 16, 2021, we enrolled 96 patients with R/R AML, including 37 primary refractory AML and 59 relapsed AML (16 relapsed after chemotherapy and 43 after allo-HSCT). The CRc rate was 70.8% (95% CI 60.8-79.2). In the patients with CRc, measurable residual disease (MRD)-negative was attained in 58.8% of CRc patients. Accordingly, overall response rate (ORR, CRc plus partial remission (PR)) was 78.1% (95% CI 68.6-85.4). At a median follow-up of 14.7 months (95% CI 6.6-22.8) for all patients, median overall survival (OS) was 22.1 months (95% CI 12.7-Not estimated), and event-free survival (EFS) was 14.3 months (95% CI 7.0-Not estimated). The 1-year OS was 61.5% (95% CI 51.0-70.4), and EFS was 51.0% (95% CI 40.7-60.5). The most common grade 3-4 adverse events were febrile neutropenia (37.4%), sepsis (11.4%), and pneumonia (21.9%).
    CONCLUSIONS: VAH is a promising and well-tolerated regimen in R/R AML, with high CRc and encouraging survival. Further randomized studies are needed to be explored. Trial registration clinicaltrials.gov identifier: NCT04424147.
    Keywords:  Acute myeloid leukemia; Azacitidine; Homoharringtonine; Refractory; Relapsed; Venetoclax
    DOI:  https://doi.org/10.1186/s13045-023-01437-1
  14. Cancer Discov. 2023 May 04. pii: CD-22-1315. [Epub ahead of print]
    An African-specific variant of TP53 reveals PADI4 as a regulator of p53-mediated tumor suppression.
    Alexandra Indeglia, Jessica C Leung, Sven A Miller, Julia I-Ju Leu, James F Dougherty, Nicole L Clarke, Nicole A Kirven, Chunlei Shao, Lei Ke, Scott Lovell, Thibaut Barnoud, David Y Lu, Cindy Lin, Toshitha Kannan, Kevin P Battaile, Tyler Hong Loong Yang, Isabela Batista Oliva, Daniel T Claiborne, Peter Vogel, Lijun Liu, Qin Liu, Yulia Nefedova, Joel Cassel, Noam Auslander, Andrew V Kossenkov, John Karanicolas, Maureen E Murphy.
      TP53 is the most frequently mutated gene in cancer, yet key target genes for p53-mediated tumor suppression remain unidentified. Here, we characterize a rare, African-specific, germline variant of TP53 in the DNA binding domain, Tyr107His (Y107H). NMR and crystal structures reveal that Y107H is structurally similar to wild-type p53. Consistent with this we find that Y107H can suppress tumor colony formation and is impaired for the transactivation of only a small subset of p53 target genes; this includes the epigenetic modifier PADI4, which deiminates arginine to the non-natural amino acid citrulline. Surprisingly, we show that Y107H mice develop spontaneous cancers and metastases, and that Y107H shows impaired tumor suppression in two other models. We show that PADI4 is itself tumor suppressive, and that it requires an intact immune system for tumor suppression. We identify a p53-PADI4 gene signature that is predictive of survival and the efficacy of immune checkpoint inhibitors.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-1315
  15. Ann Hematol. 2023 Apr 29.
    Switching from imatinib to nilotinib plus pegylated interferon-α2b in chronic phase CML failing to achieve deep molecular response: clinical and immunological effects.
    Inge G P Geelen, Stein-Erik Gullaksen, Mette M Ilander, Ulla Olssen-Strömberg, Satu Mustjoki, Johan Richter, Nicole M A Blijlevens, Willem M Smit, Bjorn T Gjertsen, Tobias Gedde-Dahl, Berit Markevärn, Malika M A Koppes, Peter E Westerweel, Henrik Hjorth-Hansen, Jeroen J W M Janssen.
      In order to improve molecular response for a discontinuation attempt in chronic myeloid leukemia (CML) patients in chronic phase, who had not achieved at least a molecular response <0.01% BCR-ABL1IS (MR4.0) after at least 2 years of imatinib therapy, we prospectively evaluated whether they could attain MR4.0 after a switch to a combination of nilotinib and 9 months of pegylated interferon-α2b (PegIFN). The primary endpoint of confirmed MR4.0 at month 12 (a BCR-ABL1IS level ≤ 0.01% both at 12 and 15 months) was reached by 44% (7/16 patients, 95% confidence interval (CI): 23- 67%) of patients, with 81% (13/16 patients, 95% CI: 57-93%) of patients achieving an unconfirmed MR4.0. The scheduled combination was completed by 56% of the patients, with premature discontinuations, mainly due to mood disturbances after the introduction of PegIFN, questioning the feasibility of the combination of nilotinib and PegIFN for this patient population and treatment goal. A comprehensive clinical substudy program was implemented to characterize the impact of the treatment changes on the immunological profile. This trial was registered at www.clinicaltrials.gov as #NCT01866553.
    Keywords:  Chronic myeloid leukemia; Immunology; Molecular response; Nilotinib; Pegylated interferon-alfa2b; Quality of life
    DOI:  https://doi.org/10.1007/s00277-023-05199-1
  16. Pharmacoeconomics. 2023 May 02.
    Oral Azacitidine for Maintenance Treatment of Acute Myeloid Leukaemia After Induction Therapy: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.
    Willem Witlox, Sabine Grimm, Jeremy Howick, Nigel Armstrong, Charlotte Ahmadu, Kevin McDermott, Thomas Otten, Caro Noake, Robert Wolff, Manuela Joore.
      The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Celgene) of oral azacitidine (ONUREG), as part of the Single Technology Appraisal (STA) process, to submit evidence for the clinical effectiveness and cost-effectiveness of oral azacitidine for maintenance treatment of acute myeloid leukaemia (AML) after induction therapy compared with watch-and-wait plus best supportive care (BSC) and midostaurin. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarises the company submission (CS), presents the ERG's critical review on the clinical and cost-effectiveness evidence in the CS, highlights the key methodological considerations and describes the development of the NICE guidance by the Appraisal Committee. In the QUAZAR AML-001 trial, oral azacitidine significantly improved overall survival (OS) versus placebo: median OS gain of 9.9 months (24.7 months versus 14.8 months; hazard ratio (HR) 0.69 (95% CI 0.55-0.86), p < 0.001). The median time to relapse was also better for oral azacitidine, and the incidences of TEAEs were similar for the two arms. The company excluded two of the comparators listed in the scope, low-dose cytarabine and subcutaneous azacitidine, informed only by clinical expert opinion, leaving only best supportive care (BSC) and midostaurin for the FLT3-ITD and/or FLT3-TKD (FLT3 mutation)-positive subgroup. An ITC comparing oral azacitidine to midostaurin as maintenance therapy in the appropriate subgroup demonstrated that the OS and relapse-free survival (RFS) HRs were favourable for oral azacitidine when compared with midostaurin. However, in the only available trial of midostaurin as maintenance treatment in AML that was used for this ITC, subjects were not randomised at the maintenance phase, but at induction, which posed a substantial risk of bias. The revised and final probabilistic incremental cost-effectiveness ratio (ICER) presented by the company, including a commercial arrangement, was £32,480 per quality-adjusted life year (QALY) gained for oral azacitidine versus watch-and-wait plus BSC. Oral azacitidine was dominant versus midostaurin in the FLT-3 subgroup. The ERG's concerns included the approach of modelling haematopoietic stem cell transplantation (HSCT), the generalisability of the population and the number of cycles of consolidation therapy pre-treatment in the QUAZAR AML-001 trial to UK clinical practice, and uncertainty in the relapse utility. The revised and final ERG base case resulted in a similar probabilistic ICER of £33,830 per QALY gained versus watch-and-wait plus BSC, but with remaining uncertainty. Oral azacitidine remained dominant versus midostaurin in the FLT-3 subgroup. After the second NICE appraisal committee meeting, the NICE Appraisal Committee recommended oral azacitidine (according to the commercial arrangement), within its marketing authorisation, as an option for maintenance treatment for AML in adults who are in complete remission, or complete remission with incomplete blood count recovery, after induction therapy with or without consolidation treatment, and cannot have or do not want HSCT.
    DOI:  https://doi.org/10.1007/s40273-023-01272-9
  17. Cell. 2023 Apr 27. pii: S0092-8674(23)00332-X. [Epub ahead of print]
    Massively parallel base editing to map variant effects in human hematopoiesis.
    Jorge D Martin-Rufino, Nicole Castano, Michael Pang, Emanuelle I Grody, Samantha Joubran, Alexis Caulier, Lara Wahlster, Tongqing Li, Xiaojie Qiu, Anna Maria Riera-Escandell, Gregory A Newby, Aziz Al'Khafaji, Santosh Chaudhary, Susan Black, Chen Weng, Glen Munson, David R Liu, Marcin W Wlodarski, Kacie Sims, Jamie H Oakley, Ross M Fasano, Ramnik J Xavier, Eric S Lander, Daryl E Klein, Vijay G Sankaran.
      Systematic evaluation of the impact of genetic variants is critical for the study and treatment of human physiology and disease. While specific mutations can be introduced by genome engineering, we still lack scalable approaches that are applicable to the important setting of primary cells, such as blood and immune cells. Here, we describe the development of massively parallel base-editing screens in human hematopoietic stem and progenitor cells. Such approaches enable functional screens for variant effects across any hematopoietic differentiation state. Moreover, they allow for rich phenotyping through single-cell RNA sequencing readouts and separately for characterization of editing outcomes through pooled single-cell genotyping. We efficiently design improved leukemia immunotherapy approaches, comprehensively identify non-coding variants modulating fetal hemoglobin expression, define mechanisms regulating hematopoietic differentiation, and probe the pathogenicity of uncharacterized disease-associated variants. These strategies will advance effective and high-throughput variant-to-function mapping in human hematopoiesis to identify the causes of diverse diseases.
    Keywords:  base editing; differentiation; functional screens; genome engineering; hematopoiesis; hematopoietic stem cell; primary cells; single-cell genomics
    DOI:  https://doi.org/10.1016/j.cell.2023.03.035
  18. Br J Haematol. 2023 May 04.
    Molecular-defined clonal evolution in patients with classical myeloproliferative neoplasms.
    Anna Hinze, Jenny Rinke, Carl C Crodel, Susanne Möbius, Vivien Schäfer, Florian H Heidel, Andreas Hochhaus, Thomas Ernst.
      Classical myeloproliferative neoplasms (MPNs) are characterized by distinct clinical phenotypes. The discovery of driver mutations in JAK2, CALR and MPL genes provided new insights into their pathogenesis. Next-generation sequencing (NGS) identified additional somatic mutations, most frequently in epigenetic modulator genes. In this study, a cohort of 95 MPN patients was genetically characterized using targeted NGS. Clonal hierarchies of detected mutations were subsequently analysed using colony forming progenitor assays derived from single cells to study mutation acquisition. Further, the hierarchy of mutations within distinct cell lineages was evaluated. NGS revealed mutations in three epigenetic modulator genes (TET2, DNMT3A, ASXL1) as most common co-mutations to the classical driver mutations. JAK2V617F as well as DNMT3A and TET2 mutations were detected as primary events in disease formation and most cases presented with a linear mutation pattern. Mutations appear mostly in the myeloid lineages but can also appear in lymphoid subpopulations. In one case with a double mutant MPL gene, mutations exclusively appeared in the monocyte lineage. Overall, this study confirms the mutational heterogeneity of classical MPNs and highlights the role of JAK2V617F and epigenetic modifier genes as early events in hematologic disease formation.
    Keywords:  DNMT3A; JAK2; MPN; TET2; clonal evolution; clonal hierarchy; single cells
    DOI:  https://doi.org/10.1111/bjh.18834
  19. Haematologica. 2023 May 04.
    Maintenance therapy in acute myeloid leukemia: advances and controversies.
    Jayastu Senapati, Tapan M Kadia, Farhad Ravandi.
      The last decade has seen a steadfast progression in drug development in acute myeloid leukemia (AML) which have moved progressively towards genomics-based therapy. With these advancements, outcomes in AML have improved but remains far from satisfactory. An approach towards preventing relapse in AML is the use of a maintenance therapy in patients, after attaining remission. Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective post-remission therapy that has been proven to reduce the risk of relapse. However, in patients who are ineligible for HSCT or have a high risk of relapse, other effective measures to prevent relapse are needed. There also exists a need for post HSCT maintenance to reduce relapse in high-risk subsets. Over the last 3 decades maintenance therapy in AML has evolved from the use of chemotherapeutic agents to more targeted therapies and better modulation of the immune system. Unfortunately, improvement in survival outcomes from these agents have not been consistently demonstrated in clinical trials. To derive the optimum benefit from maintenance therapy the time points of therapy initiation need to be defined and therapy selection must be precise with respect to the AML genetics and risk stratification, prior treatment exposure, transplant eligibility, expected toxicity and patient's clinical profile and desires. The far-reaching goal is to facilitate patients with AML in remission to achieve a normal quality of life while improving remission duration and overall survival. The QUAZAR trial was a welcome step towards a safe maintenance drug with ease of administration and showed survival benefit but leaves many open issues for discussion. In this review we will discuss these issues, highlighting the development of AML maintenance therapies over the last 3 decades.
    DOI:  https://doi.org/10.3324/haematol.2022.281810
  20. Leukemia. 2023 Apr 29.
    Glucose partitioning in the bone marrow micro-environment in acute myeloid leukaemia.
    Suqi Deng, Juan Du, Robert Peter Gale, Lu Wang, Huien Zhan, Fangshu Liu, Kexiu Huang, Hao Xu, Hui Zeng.
      Acute myeloid leukaemia (AML) cells metabolise glucose by glycolysis-based re-programming. However, how glucose uptake is partitioned between leukaemia cells and other cells of the bone marrow micro-environment is unstudied. We used a positron emission tomography (PET) tracer 18F fluorodeoxyglucose ([18F]-FDG) probe and transcriptomic analyses to detect glucose uptake by diverse cells in the bone marrow micro-environment in a MLL-AF9-induced mouse model. Leukaemia cells had the greatest glucose uptake with leukaemia stem and progenitor cells having the greatest glucose uptake. We also show the effects of anti-leukaemia drugs on leukaemia cell numbers and glucose uptake. Our data suggest targeting glucose uptake as a potential therapy strategy in AML if our observations are validated in humans with AML.
    DOI:  https://doi.org/10.1038/s41375-023-01912-1
  21. Haematologica. 2023 May 04.
    Germline loss of function BRCA1 and BRCA2 mutations and risk of de novo hematopoietic malignancies.
    Ryan J Stubbins, Anase S Asom, Peng Wang, Angela M Lager, Alexander Gary, Lucy A Godley.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2022.281580
  22. Leukemia. 2023 May 05.
    NUP98::Nsd1 and FLT3-ITD collaborate to generate acute myeloid leukemia.
    Toshihiro Matsukawa, Mianmian Yin, Nupur Nigam, Vijay Negi, Li Li, Donald Small, Yuelin J Zhu, Robert L Walker, Paul S Meltzer, Peter D Aplan.
      
    DOI:  https://doi.org/10.1038/s41375-023-01913-0
  23. N Engl J Med. 2023 May 04.
    Telomere Length and Clonal Hematopoiesis.
    George Vassiliou.
      
    DOI:  https://doi.org/10.1056/NEJMe2303022
  24. Cell Stem Cell. 2023 May 04. pii: S1934-5909(23)00130-3. [Epub ahead of print]30(5): 722-740.e11
    GTAC enables parallel genotyping of multiple genomic loci with chromatin accessibility profiling in single cells.
    Sven Turkalj, Niels Asger Jakobsen, Angus Groom, Marlen Metzner, Simone G Riva, E Ravza Gür, Batchimeg Usukhbayar, Mirian Angulo Salazar, Lance D Hentges, Gerda Mickute, Kevin Clark, Paul Sopp, James O J Davies, Jim R Hughes, Paresh Vyas.
      Understanding clonal evolution and cancer development requires experimental approaches for characterizing the consequences of somatic mutations on gene regulation. However, no methods currently exist that efficiently link high-content chromatin accessibility with high-confidence genotyping in single cells. To address this, we developed Genotyping with the Assay for Transposase-Accessible Chromatin (GTAC), enabling accurate mutation detection at multiple amplified loci, coupled with robust chromatin accessibility readout. We applied GTAC to primary acute myeloid leukemia, obtaining high-quality chromatin accessibility profiles and clonal identities for multiple mutations in 88% of cells. We traced chromatin variation throughout clonal evolution, showing the restriction of different clones to distinct differentiation stages. Furthermore, we identified switches in transcription factor motif accessibility associated with a specific combination of driver mutations, which biased transformed progenitors toward a leukemia stem cell-like chromatin state. GTAC is a powerful tool to study clonal heterogeneity across a wide spectrum of pre-malignant and neoplastic conditions.
    Keywords:  acute myeloid leukemia; cancer evolution; chromatin accessibility; clonal tracking; epigenomics; leukemia stem cells; single-cell ATAC-seq; single-cell technologies; somatic mutation; tumor heterogeneity
    DOI:  https://doi.org/10.1016/j.stem.2023.04.012
  25. Blood. 2023 May 04. 141(18): 2283
    BCOR/BCORL1 mutated hypergranular cells mimicking acute promyelocytic leukemia.
    Benjamin Lebecque, Louis-Thomas Dannus.
      
    DOI:  https://doi.org/10.1182/blood.2022019204
  26. Dev Cell. 2023 Apr 25. pii: S1534-5807(23)00160-0. [Epub ahead of print]
    Transcription factor induction of vascular blood stem cell niches in vivo.
    Elliott J Hagedorn, Julie R Perlin, Rebecca J Freeman, Samuel J Wattrus, Tianxiao Han, Clara Mao, Ji Wook Kim, Inés Fernández-Maestre, Madeleine L Daily, Christopher D'Amato, Michael J Fairchild, Raquel Riquelme, Brian Li, Dana A V E Ragoonanan, Khaliun Enkhbayar, Emily L Henault, Helen G Wang, Shelby E Redfield, Samantha H Collins, Asher Lichtig, Song Yang, Yi Zhou, Balvir Kunar, Jesus Maria Gomez-Salinero, Thanh T Dinh, Junliang Pan, Karoline Holler, Henry A Feldman, Eugene C Butcher, Alexander van Oudenaarden, Shahin Rafii, J Philipp Junker, Leonard I Zon.
      The hematopoietic niche is a supportive microenvironment composed of distinct cell types, including specialized vascular endothelial cells that directly interact with hematopoietic stem and progenitor cells (HSPCs). The molecular factors that specify niche endothelial cells and orchestrate HSPC homeostasis remain largely unknown. Using multi-dimensional gene expression and chromatin accessibility analyses in zebrafish, we define a conserved gene expression signature and cis-regulatory landscape that are unique to sinusoidal endothelial cells in the HSPC niche. Using enhancer mutagenesis and transcription factor overexpression, we elucidate a transcriptional code that involves members of the Ets, Sox, and nuclear hormone receptor families and is sufficient to induce ectopic niche endothelial cells that associate with mesenchymal stromal cells and support the recruitment, maintenance, and division of HSPCs in vivo. These studies set forth an approach for generating synthetic HSPC niches, in vitro or in vivo, and for effective therapies to modulate the endogenous niche.
    Keywords:  blood stem cell niche; hematopoietic development; niche endothelial cells; reprogramming; vascular endothelium; zebrafish
    DOI:  https://doi.org/10.1016/j.devcel.2023.04.007
  27. PLoS Biol. 2023 05;21(5): e3001746
    Tumor-derived interleukin-1α and leukemia inhibitory factor promote extramedullary hematopoiesis.
    Derek A G Barisas, Ashraf Ul Kabir, Jun Wu, Karen Krchma, Minseo Kim, Madhav Subramanian, Bernd H Zinselmeyer, Colin L Stewart, Kyunghee Choi.
      Extramedullary hematopoiesis (EMH) expands hematopoietic capacity outside of the bone marrow in response to inflammatory conditions, including infections and cancer. Because of its inducible nature, EMH offers a unique opportunity to study the interaction between hematopoietic stem and progenitor cells (HSPCs) and their niche. In cancer patients, the spleen frequently serves as an EMH organ and provides myeloid cells that may worsen pathology. Here, we examined the relationship between HSPCs and their splenic niche in EMH in a mouse breast cancer model. We identify tumor produced IL-1α and leukemia inhibitory factor (LIF) acting on splenic HSPCs and splenic niche cells, respectively. IL-1α induced TNFα expression in splenic HSPCs, which then activated splenic niche activity, while LIF induced proliferation of splenic niche cells. IL-1α and LIF display cooperative effects in activating EMH and are both up-regulated in some human cancers. Together, these data expand avenues for developing niche-directed therapies and further exploring EMH accompanying inflammatory pathologies like cancer.
    DOI:  https://doi.org/10.1371/journal.pbio.3001746
  28. Sci Adv. 2023 May 03. 9(18): eadf0138
    Inter-organelle cross-talk supports acetyl-coenzyme A homeostasis and lipogenesis under metabolic stress.
    Ramya S Kuna, Avi Kumar, Karl A Wessendorf-Rodriguez, Hector Galvez, Courtney R Green, Grace H McGregor, Thekla Cordes, Reuben J Shaw, Robert U Svensson, Christian M Metallo.
      Proliferating cells rely on acetyl-CoA to support membrane biogenesis and acetylation. Several organelle-specific pathways are available for provision of acetyl-CoA as nutrient availability fluctuates, so understanding how cells maintain acetyl-CoA homeostasis under such stresses is critically important. To this end, we applied 13C isotope tracing cell lines deficient in these mitochondrial [ATP-citrate lyase (ACLY)]-, cytosolic [acetyl-CoA synthetase (ACSS2)]-, and peroxisomal [peroxisomal biogenesis factor 5 (PEX5)]-dependent pathways. ACLY knockout in multiple cell lines reduced fatty acid synthesis and increased reliance on extracellular lipids or acetate. Knockout of both ACLY and ACSS2 (DKO) severely stunted but did not entirely block proliferation, suggesting that alternate pathways can support acetyl-CoA homeostasis. Metabolic tracing and PEX5 knockout studies link peroxisomal oxidation of exogenous lipids as a major source of acetyl-CoA for lipogenesis and histone acetylation in cells lacking ACLY, highlighting a role for inter-organelle cross-talk in supporting cell survival in response to nutrient fluctuations.
    DOI:  https://doi.org/10.1126/sciadv.adf0138
  29. Nat Chem Biol. 2023 May 01.
    Acetyl-CoA biosynthesis drives resistance to histone acetyltransferase inhibition.
    Timothy R Bishop, Chitra Subramanian, Eric M Bilotta, Leopold Garnar-Wortzel, Anissa R Ramos, Yuxiang Zhang, Joshua N Asiaban, Christopher J Ott, Charles O Rock, Michael A Erb.
      Histone acetyltransferases (HATs) are implicated as both oncogene and nononcogene dependencies in diverse human cancers. Acetyl-CoA-competitive HAT inhibitors have emerged as potential cancer therapeutics and the first clinical trial for this class of drugs is ongoing (NCT04606446). Despite these developments, the potential mechanisms of therapeutic response and evolved drug resistance remain poorly understood. Having discovered that multiple regulators of de novo coenzyme A (CoA) biosynthesis can modulate sensitivity to CBP/p300 HAT inhibition (PANK3, PANK4 and SLC5A6), we determined that elevated acetyl-CoA concentrations can outcompete drug-target engagement to elicit acquired drug resistance. This not only affects structurally diverse CBP/p300 HAT inhibitors, but also agents related to an investigational KAT6A/B HAT inhibitor that is currently in Phase 1 clinical trials. Altogether, this work uncovers CoA metabolism as an unexpected liability of anticancer HAT inhibitors and will therefore buoy future efforts to optimize the efficacy of this new form of targeted therapy.
    DOI:  https://doi.org/10.1038/s41589-023-01320-7
  30. SLAS Discov. 2023 Apr 28. pii: S2472-5552(23)00035-7. [Epub ahead of print]
    High-throughput Approaches to Uncover Synergistic Drug Combinations in Leukemia.
    Emma J Chory, Meng Wang, Michele Ceribelli, Aleksandra M Michalowska, Stefan Golas, Erin Beck, Carleen Klumpp-Thomas, Lu Chen, Crystal McKnight, Zina Itkin, Kelli M Wilson, David Holland, Sanjay Divakaran, James Bradner, Javed Khan, Berkley E Gryder, Craig J Thomas, Benjamin Z Stanton.
      We report a comprehensive drug synergy study in acute myeloid leukemia (AML). In this work, we investigate a panel of cell lines spanning both MLL-rearranged and non-rearranged subtypes. The work comprises a resource for the community, with many synergistic drug combinations that could not have been predicted a priori, and open source code for automation and analyses. We base our definitions of drug synergy on the Chou-Talalay method, which is useful for visualizations of synergy experiments in isobolograms, and median-effects plots, among other representations. Our key findings include drug synergies affecting the chromatin state, specifically in the context of regulation of the modification state of histone H3 lysine-27. We report open source high throughput methodology such that multidimensional drug screening can be accomplished with equipment that is accessible to most laboratories. This study will enable preclinical investigation of new drug combinations in a lethal blood cancer, with data analysis and automation workflows freely available to the community.
    Keywords:  Acute Myeloid Leukemia; Combination Index; Combination Therapy; Epigenetics; Open-source Automation; Precision Medicine; Synergy
    DOI:  https://doi.org/10.1016/j.slasd.2023.04.004
  31. Blood. 2023 May 04. 141(18): 2168-2170
    NFIA-ETO2, TP53, and erythroid leukemogenesis.
    Benjamin J Huang, Kevin Shannon.
      
    DOI:  https://doi.org/10.1182/blood.2023019856
  32. FEBS J. 2023 Apr 29.
    Cytoplasmic Localization of Mdm2 in Cells Expressing Mutated NPM is Mediated by p53.
    Dita Strachotová, Aleš Holoubek, Kateřina Wolfová, Barbora Brodská, Petr Heřman.
      Specific C-terminal nucleophosmin (NPM) mutations are related to the acute myeloid leukemia and cause mistargeting of mutated NPM (NPMmut) to the cytoplasm. Consequently, multiple NPM-interacting partners, e.g. the tumor suppressor p53, become also mislocalized. We found that ubiquitin ligase Mdm2 mislocalizes to the cytoplasm in the presence of NPMmut as well. Since p53 interacts with Mdm2, we searched for the NPMmut-p53-Mdm2 complex and interactions of its constituents in live cells and cell lysates using fluorescently tagged proteins, fluorescence lifetime imaging and immunoprecipitation. We proved existence of the ternary complex, which likely adopts a chain-like configuration. Interaction between Mdm2 and NPMmut was not detected, even under conditions of upregulated Mdm2 and p53 induced by Actinomycin D. We assume that p53 serves in the complex as a bridging link between Mdm2 and NPMmut. This conclusion was supported by disruption of the Mdm2-p53 interaction by Nutlin-3A, which resulted in a relocalization of Mdm2 to the nucleus, while both NPMmut and p53 remained in the cytoplasm. Importantly, silencing of p53 also prevented mislocalization of Mdm2 in the presence of NPMmut.
    Keywords:  FRET-FLIM; Mdm2; Nucleophosmin mutation; acute myeloid leukemia; p53
    DOI:  https://doi.org/10.1111/febs.16810
  33. Leuk Res. 2023 Apr 23. pii: S0145-2126(23)00064-4. [Epub ahead of print]129 107299
    Ponatinib, asciminib and inotuzumab ozogamicin: A novel drug combination in acute lymphoblastic leukemia.
    Jose Tinajero, Paul Koller, Haris Ali.
      
    Keywords:  Acute lymphoblastic leukemia; Asciminib; Hemodialysis; Ponatinib; Tyrosine kinase inhibitor
    DOI:  https://doi.org/10.1016/j.leukres.2023.107299
  34. N Engl J Med. 2023 May 04.
    Familial Clonal Hematopoiesis in a Long Telomere Syndrome.
    Emily A DeBoy, Michael G Tassia, Kristen E Schratz, Stephanie M Yan, Zoe L Cosner, Emily J McNally, Dustin L Gable, Zhimin Xiang, David B Lombard, Emmanuel S Antonarakis, Christopher D Gocke, Rajiv C McCoy, Mary Armanios.
      BACKGROUND: Telomere shortening is a well-characterized cellular aging mechanism, and short telomere syndromes cause age-related disease. However, whether long telomere length is advantageous is poorly understood.METHODS: We examined the clinical and molecular features of aging and cancer in persons carrying heterozygous loss-of-function mutations in the telomere-related gene POT1 and noncarrier relatives.
    RESULTS: A total of 17 POT1 mutation carriers and 21 noncarrier relatives were initially included in the study, and a validation cohort of 6 additional mutation carriers was subsequently recruited. A majority of the POT1 mutation carriers with telomere length evaluated (9 of 13) had long telomeres (>99th percentile). POT1 mutation carriers had a range of benign and malignant neoplasms involving epithelial, mesenchymal, and neuronal tissues in addition to B- and T-cell lymphoma and myeloid cancers. Five of 18 POT1 mutation carriers (28%) had T-cell clonality, and 8 of 12 (67%) had clonal hematopoiesis of indeterminate potential. A predisposition to clonal hematopoiesis had an autosomal dominant pattern of inheritance, as well as penetrance that increased with age; somatic DNMT3A and JAK2 hotspot mutations were common. These and other somatic driver mutations probably arose in the first decades of life, and their lineages secondarily accumulated a higher mutation burden characterized by a clocklike signature. Successive generations showed genetic anticipation (i.e., an increasingly early onset of disease). In contrast to noncarrier relatives, who had the typical telomere shortening with age, POT1 mutation carriers maintained telomere length over the course of 2 years.
    CONCLUSIONS: POT1 mutations associated with long telomere length conferred a predisposition to a familial clonal hematopoiesis syndrome that was associated with a range of benign and malignant solid neoplasms. The risk of these phenotypes was mediated by extended cellular longevity and by the capacity to maintain telomeres over time. (Funded by the National Institutes of Health and others.).
    DOI:  https://doi.org/10.1056/NEJMoa2300503
  35. Am J Hematol. 2023 May 02.
    Imatinib compared with second-generation tyrosine kinase-inhibitors in persons with chronic myeloid leukemia presenting in accelerated phase.
    Sen Yang, Xiaoshuai Zhang, Robert Peter Gale, Xin Du, Chun-Yan Chen, Jian-Yu Weng, Jian Huang, Fei Li, Yun Zeng, Zhen Xiao, Jian-da Hu, Li-Jie Yang, Zhuo-Gang Liu, Guo-Hui Li, Xiu-Li Sun, Wei Yang, Ru Feng, Yan-Qiu Han, Yu Jing, Na Xu, Xiao-Li Liu, Zhen-Fang Liu, Xiao-Dong Wang, Shi-Xin Wu, Rong Liang, Yan-Li Zhang, Yun-Fan Yang, Huan-Ling Zhu, Ling Pan, Li Meng, Yan-Hong Zhao, Hai Yi, Yi-Lan Liu, Wei-Hua Zhang, Yuan-Jun Zheng, Ze-Ping Zhou, Su-Ning Chen, Hui-Ying Qiu, Wei-Ming Li, Zhi-Lin Jia, Yan-Liang Bai, Li-E Lin, Bing-Cheng Liu, Chun-Shui Liu, Jian-Min Luo, Jun-Xia Meng, Zhi-Qiang Sun, Yan-Qing Zhang, Xiao-Jun Huang, Qian Jiang.
      
    DOI:  https://doi.org/10.1002/ajh.26943
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