bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2023–05–14
twenty-two papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. A Randomised Comparison of CPX-351 and FLAG-Ida in Adverse Karyotype AML and High-Risk MDS: The UK NCRI AML19 Trial.
  2. Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and purine biosynthesis.
  3. CD69 marks a subpopulation of acute myeloid leukemia with enhanced colony forming capacity and a unique signaling activation state.
  4. A novel lncRNA SNHG29 regulates EP300- related histone acetylation modification and inhibits FLT3-ITD AML development.
  5. FLT3-ITD does not predict inferior prognosis in acute myeloid leukemia patients age ≥60 years.
  6. Paralog-specific signaling by IRAK1/4 maintains MyD88-independent functions in MDS/AML.
  7. Integrative molecular subtypes of acute myeloid leukemia.
  8. NPM1-mutated AML with starry sky pattern.
  9. Outcomes of graft failure after umbilical cord blood transplantation in acute leukemia: a study from Eurocord and the Acute Leukemia Working Party of the EBMT.
  10. Safety and efficacy of zinpentraxin alfa as monotherapy or in combination with ruxolitinib in myelofibrosis: stage I of a phase II trial.
  11. Single-Cell Profiling of CD8+ T Cells in Acute Myeloid Leukemia Reveals a Continuous Spectrum of Differentiation and Clonal Hyperexpansion.
  12. Real-world genomic profiling of acute myeloid leukemia and the impact of European LeukemiaNet risk stratification 2022 update.
  13. Targeting leukemia with a metabolic genotoxin.
  14. Mast cell deficiency prevents BCR::ABL1 induced splenomegaly and cytokine elevation in a CML mouse model.
  15. Impact of Clonal Architecture on Clinical Course and Prognosis in Patients With Myeloproliferative Neoplasms.
  16. CD38 as a pan-hematologic target for chimeric antigen receptor T cells.
  17. Impact of secondary-type mutations in NPM1 mutated AML.
  18. The orally bioavailable GSPT1/2 degrader SJ6986 exhibits in vivo efficacy in acute lymphoblastic leukemia.
  19. Second haploidentical stem cell transplantation (HAPLO-SCT2) after relapse from a first HAPLO-SCT in acute leukaemia-a study on behalf of the Acute Leukaemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT).
  20. Metformin exerts antileukemic effects by modulating lactate metabolism and overcomes imatinib resistance in chronic myeloid leukemia.
  21. Therapies for acute myeloid leukemia in patients ineligible for standard induction chemotherapy: a systematic review.
  22. Mutation signatures reveal clonal evolution.
  1. Blood Adv. 2023 May 12. pii: bloodadvances.2023010276. [Epub ahead of print]
    A Randomised Comparison of CPX-351 and FLAG-Ida in Adverse Karyotype AML and High-Risk MDS: The UK NCRI AML19 Trial.
    Jad Othman, Charlotte S Wilhelm-Benartzi, Richard Dillon, Steven Knapper, Sylvie D Freeman, Leona M Batten, Joanna Canham, Emily L Hinson, Julie Wych, Sophie Betteridge, William Villiers, Michelle Kleeman, Amanda Frances Gilkes, Nicola Potter, Ulrik Overgaard, Priyanka Mehta, Panagiotis Kottaridis, Jamie Cavenagh, Claire Jane Hemmaway, Claire Arnold, Mike Dennis, Nigel H Russell.
      Liposomal daunorubicin and cytarabine (CPX-351) improves overall survival (OS) compared to 7+3 chemotherapy in older patients with secondary acute myeloid leukaemia (AML); to date there have been no randomized studies in younger patients. The high-risk cohort of the UK NCRI AML19 trial (ISRCTN78449203) compared CPX-351 with FLAG-Ida in younger adults with newly-diagnosed adverse cytogenetic AML or high-risk myelodysplastic syndromes (MDS). 189 patients were randomized (median age 56y). By clinical criteria 49% had de novo AML, 20% secondary AML and 30% high risk MDS. MDS-related cytogenetics were present in 73% of patients, with complex karyotype in 49%. TP53 was the most commonly mutated gene, in 43%. Myelodysplasia-related gene mutations were present in 75 patients (44%). The overall response rate (CR + CRi) after course two was 64% and 76% for CPX-351 and FLAG-Ida (OR:0.54, 95%CI 0.28-1.04, p=0.06). There was no difference in OS (13.3 months vs 11.4 months, HR:0.78, 95%CI 0.55-1.12, p=0.17) or event-free survival (HR:0.90, 95%CI 0.64-1.27, p=0.55) in multivariable analyses. However, relapse-free survival was significantly longer with CPX-351 (median 22.1 vs 8.35 months, HR:0.58, 95% CI 0.36-0.95, p=0.03). There was no difference between the treatment arms in patients with clinically defined secondary AML (HR:1.1, 95%CI 0.52-2.30) or those with MDS-related cytogenetic abnormalities (HR:0.94, 95%CI 0.63-1.40), however an exploratory sub-group of patients with MDS-related gene mutations had significantly longer OS with CPX-351 (median 38.4 vs 16.3 months, HR:0.42, 95%CI 0.21-0.84, heterogeneity p=0.05). In conclusion, OS in younger patients with adverse risk AML/MDS was not significantly different between CPX-351 and FLAG-Ida.
    DOI:  https://doi.org/10.1182/bloodadvances.2023010276
  2. Res Sq. 2023 Apr 28. pii: rs.3.rs-2843025. [Epub ahead of print]
    Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and purine biosynthesis.
    Natalia Baran, Katie Hurrish, Yongwei Su, Shraddha Patel, Cassandra Ramage, Jenna Carter, Holly Edwards, Steven Buck, Sandra Wiley, Maik Hüttemann, Lisa Polin, Juiwanna Kushner, Sijana Dzinic, Kathryn White, Xun Bao, Jing Li, Jay Yang, Julie Boerner, Zhanjun Hou, Gheath Al-Atrash, Sergej Konoplev, Jonathan Busquets, Stefano Tiziani, Larry Matherly, Jeffrey Taub, Marina Konopleva, Yubin Ge.
      Venetoclax (VEN), in combination with low dose cytarabine (AraC) or a hypomethylating agent, is FDA approved to treat acute myeloid leukemia (AML) in patients who are over the age of 75 or cannot tolerate standard chemotherapy. Despite high response rates to these combination therapies, most patients succumb to the disease due to relapse and/or drug resistance, providing an unmet clinical need for novel therapies to improve AML patient survival. ME-344 is a potent isoflavone with demonstrated inhibitory activity toward oxidative phosphorylation (OXPHOS) and clinical activity in solid tumors. Given that OXPHOS inhibition enhances VEN antileukemic activity against AML, we hypothesized that ME-344 could enhance the anti-AML activity of VEN. Here we report that ME-344 synergized with VEN to target AML cell lines and primary patient samples while sparing normal hematopoietic cells. Cooperative suppression of OXPHOS was detected in a subset of AML cell lines and primary patient samples. Metabolomics analysis revealed a significant reduction of purine biosynthesis metabolites by ME-344. Further, lometrexol, an inhibitor of purine biosynthesis, synergistically enhanced VEN-induced apoptosis in AML cell lines. Interestingly, AML cells with acquired resistance to AraC showed significantly increased purine biosynthesis metabolites and sensitivities to ME-344. Furthermore, synergy between ME-344 and VEN was preserved in these AraC-resistant AML cells. These results translated into significantly prolonged survival upon combination of ME-344 and VEN in NSGS mice bearing parental or AraC-resistant MV4-11 leukemia. This study demonstrates that ME-344 enhances VEN antileukemic activity against preclinical models of AML by suppressing OXPHOS and/or purine biosynthesis.
    DOI:  https://doi.org/10.21203/rs.3.rs-2843025/v1
  3. Leuk Lymphoma. 2023 May 10. 1-13
    CD69 marks a subpopulation of acute myeloid leukemia with enhanced colony forming capacity and a unique signaling activation state.
    Marie Lue Antony, Daniel Chang, Klara E Noble-Orcutt, Anna Kay, Jeffrey L Jensen, Hesham Mohei, Chad L Myers, Karen Sachs, Zohar Sachs.
      In acute myeloid leukemia (AML), leukemia stem cells (LSCs) have self-renewal potential and are responsible for relapse. We previously showed that, in Mll-AF9/NRASG12V murine AML, CD69 expression marks an LSC-enriched subpopulation with enhanced in vivo self-renewal capacity. Here, we used CyTOF to define activated signaling pathways in LSC subpopulations in Mll-AF9/NRASG12V AML. Furthermore, we compared the signaling activation states of CD69High and CD36High subsets of primary human AML. The human CD69High subset expresses low levels of Ki67 and high levels of NFκB and pMAPKAPKII. Additionally, the human CD69High AML subset also has enhanced colony-forming capacity. We applied Bayesian network modeling to compare the global signaling network within the human AML subsets. We find that distinct signaling states, distinguished by NFκB and pMAPKAPKII levels, correlate with divergent functional subsets, defined by CD69 and CD36 expression, in human AML. Targeting NFκB with proteasome inhibition diminished colony formation.
    Keywords:  Bayesian network; Leukemia stem cells; Neoplasia; Signal transduction; signaling
    DOI:  https://doi.org/10.1080/10428194.2023.2207698
  4. Leukemia. 2023 May 08.
    A novel lncRNA SNHG29 regulates EP300- related histone acetylation modification and inhibits FLT3-ITD AML development.
    Shan Liu, Jie Zhou, Xiangling Ye, Danni Chen, Weimin Chen, Yaobin Lin, Zhizhong Chen, Biyun Chen, Jin Shang.
      Internal tandem duplication (ITD) mutations within the FMS-like tyrosine kinase-3 (FLT3) occur in up to 25% of acute myeloid leukemia (AML) patients and indicate a very poor prognosis. The role of long noncoding RNAs (lncRNAs) in FLT3-ITD AML progression remains unexplored. We identified a novel lncRNA, SNHG29, whose expression is specifically regulated by the FLT3-STAT5 signaling pathway and is abnormally down-regulated in FLT3-ITD AML cell lines. SNHG29 functions as a tumor suppressor, significantly inhibiting FLT3-ITD AML cell proliferation and decreasing sensitivity to cytarabine in vitro and in vivo models. Mechanistically, we demonstrated that SNHG29's molecular mechanism is EP300-binding dependent and identified the EP300-interacting region of SNHG29. SNHG29 modulates genome-wide EP300 genomic binding, affecting EP300-mediated histone modification and consequently influencing the expression of varies downstream AML-associated genes. Our study uncovers a novel molecular mechanism for SNHG29 in mediating FLT3-ITD AML biological behaviors through epigenetic modification, suggesting that SNHG29 could be a potential therapeutic target for FLT3-ITD AML.
    DOI:  https://doi.org/10.1038/s41375-023-01923-y
  5. Blood Adv. 2023 May 10. pii: bloodadvances.2023009748. [Epub ahead of print]
    FLT3-ITD does not predict inferior prognosis in acute myeloid leukemia patients age ≥60 years.
    Shai Shimony, Geoffrey G Fell, Evan C Chen, Harrison K Tsai, Martha Wadleigh, Eric S Winer, Jacqueline S Garcia, Marlise R Luskin, Maximilian Stahl, Donna S Neuberg, Daniel J DeAngelo, R Coleman Lindsley, Richard M Stone.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2023009748
  6. Blood. 2023 May 12. pii: blood.2022018718. [Epub ahead of print]
    Paralog-specific signaling by IRAK1/4 maintains MyD88-independent functions in MDS/AML.
    Joshua Ruina Bennett, Chiharu Ishikawa, Puneet Agarwal, Jennifer Yeung, Avery Sampson, Emma Uible, Eric Vick, Lyndsey Bolanos, Kathleen M Hueneman, Mark Wunderlich, Amal Kolt, Kwangmin Choi, Andrew G Volk, Kenneth D Greis, Jan S Rosenbaum, Scott Hoyt, Craig J Thomas, Daniel T Starczynowski.
      Dysregulation of innate immune signaling is a hallmark of hematologic malignancies. Recent therapeutic efforts to subvert aberrant innate immune signaling in MDS and AML have focused on the kinase IRAK4. IRAK4 inhibitors have achieved promising, though moderate, responses in pre-clinical studies and in clinical trials for MDS and AML. The reasons underlying the limited responses to IRAK4 inhibitors remain unknown. Here, we reveal that inhibiting IRAK4 in leukemic cells elicits functional complementation and compensation by its paralog, IRAK1. Using genetic approaches, we demonstrate that co-targeting IRAK1 and IRAK4 is required to suppress leukemic stem/progenitor cell (LSPC) function and induce differentiation in cell lines and patient-derived cells. While IRAK1 and IRAK4 are presumed to function primarily downstream of the proximal adapter MyD88, we found that complimentary and compensatory IRAK1 and IRAK4 dependencies in MDS/AML occur via non-canonical MyD88-independent pathways. Genomic and proteomic analyses revealed that IRAK1 and IRAK4 preserve the undifferentiated state of MDS/AML LSPCs by coordinating a network of pathways, including ones that converge on the PRC2 complex and JAK-STAT signaling. To translate these findings, we implemented a structure-based design of a potent and selective dual IRAK1 and IRAK4 inhibitor KME-2780. MDS/AML cell lines and patient-derived samples showed significant suppression of LSPCs in vitro and in xenograft studies when treated with KME-2780 as compared to selective IRAK4 inhibitors. Our results provide a mechanistic basis and rationale for co-targeting IRAK1 and IRAK4 for the treatment of cancers, including MDS/AML.
    DOI:  https://doi.org/10.1182/blood.2022018718
  7. Blood Cancer J. 2023 05 08. 13(1): 71
    Integrative molecular subtypes of acute myeloid leukemia.
    Qianxing Mo, Seongseok Yun, David A Sallman, Nicole D Vincelette, Guang Peng, Ling Zhang, Jeffrey E Lancet, Eric Padron.
      
    DOI:  https://doi.org/10.1038/s41408-023-00836-4
  8. Br J Haematol. 2023 May 08.
    NPM1-mutated AML with starry sky pattern.
    Brunangelo Falini, Valeria Cardinali, Lorenzo Brunetti, Maria Paola Martelli.
      
    DOI:  https://doi.org/10.1111/bjh.18808
  9. Bone Marrow Transplant. 2023 May 10.
    Outcomes of graft failure after umbilical cord blood transplantation in acute leukemia: a study from Eurocord and the Acute Leukemia Working Party of the EBMT.
    Frédéric Baron, Annalisa Ruggeri, Christophe Peczynski, Myriam Labopin, Jean-Henri Bourhis, Mauricette Michallet, Patrice Chevallier, Jaime Sanz, Edouard Forcade, Riccardo Saccardi, Victoria Potter, Eliane Gluckman, Arnon Nagler, Mohamad Mohty.
      Graft failure has remained a limitation of umbilical cord blood transplantation (CBT). Here, we assessed the outcomes of patients who experienced graft failure after CBT. Inclusion criteria were patients (age ≥ 18 years) experiencing graft failure after unrelated CBT (single or double) between 2005 and 2016, for acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL), no prior allogeneic or autologous transplantation, no other stem cell product. The study included 87 patients. At 1-year, cumulative incidence of relapse and nonrelapse mortality (NRM) was 35% and 37%, respectively. One-year overall survival (OS) and progression-free survival (PFS) was 40% and 29%, respectively. Forty-six patients underwent a salvage second transplantation with 1-year and 2-year OS and PFS from second transplantation 41% and 34% for OS, and 37% and 34% for PFS, respectively. In multivariate analysis, complete remission (CR) at CBT (HR = 0.45, 95% CI 0.25-0.83, P = 0.01) and reduced-intensity conditioning (HR = 0.51, 95% CI 0.29-0.91, P = 0.023) were associated with better OS. In conclusion, in this retrospective study, we observed that approximately one-quarter of patients experiencing graft failure after CBT remained alive without relapse 2 years later.
    DOI:  https://doi.org/10.1038/s41409-023-02000-9
  10. Haematologica. 2023 May 11.
    Safety and efficacy of zinpentraxin alfa as monotherapy or in combination with ruxolitinib in myelofibrosis: stage I of a phase II trial.
    Srdan Verstovsek, Lynda Foltz, Vikas Gupta, Robert Hasserjian, Taghi Manshouri, John Mascarenhas, Ruben Mesa, Olga Pozdnyakova, Ellen Ritchie, Ivo Veletic, Katia Gamel, Habib Hamidi, Lyrialle Han, Brian Higgins, Kerstin Trunzer, Marianne Uguen, Dao Wang, Tarec Christoffer El-Galaly, Boyan Todorov, Jason Gotlib.
      Pentraxin 2 (PTX-2; serum amyloid P component), a circulating endogenous regulator of the inflammatory response to tissue injury and fibrosis, is reduced in patients with myelofibrosis (MF). Zinpentraxin alfa (RO7490677, PRM-151) is a recombinant form of PTX-2 that has shown preclinical antifibrotic activity and no dose-limiting toxicities in phase I trials. We report results from stage 1 of a phase II trial of zinpentraxin alfa in patients with intermediate-1/2 or high-risk MF. Patients (n=27) received intravenous zinpentraxin alfa weekly (QW) or every 4 weeks (Q4W), as monotherapy or an additional therapy for patients on stable-dose ruxolitinib. The primary endpoint was overall response rate (ORR; investigator-assessed) adapted from International Working Group-Myeloproliferative Neoplasms Research and Treatment criteria. Secondary endpoints included modified Myeloproliferative Neoplasm-Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) change, bone marrow (BM) MF grade reduction, pharmacokinetics, and safety. ORR at week 24 was 33% (n=9/27) and varied across individual cohorts (QW: 38% [3/8]; Q4W: 14% [1/7]; QW+ruxolitinib: 33% [2/6]; Q4W+ruxolitinib: 50% [3/6]). Five of 18 evaluable patients (28%) experienced a ≥50% reduction in MPN-SAF TSS, and 6/17 evaluable patients (35%) had a ≥1 grade improvement from baseline in BM fibrosis at week 24. Most treatmentemergent adverse events (AE) were grade 1-2, most commonly fatigue. Among others, anemia and thrombocytopenia were infrequent (n=3 and n=1, respectively). Treatmentrelated serious AE occurred in four patients (15%). Overall, zinpentraxin alfa showed evidence of clinical activity and tolerable safety as monotherapy and in combination with ruxolitinib in this open-label, non-randomized trial. ClinicalTrials.gov Identifier: NCT01981850.
    DOI:  https://doi.org/10.3324/haematol.2022.282411
  11. Cancer Immunol Res. 2023 May 10. pii: CIR-22-0961. [Epub ahead of print]
    Single-Cell Profiling of CD8+ T Cells in Acute Myeloid Leukemia Reveals a Continuous Spectrum of Differentiation and Clonal Hyperexpansion.
    Poonam N Desai, Bofei Wang, Andre Fonseca, Pamella Borges, Fatima Zahra Jelloul, Patrick K Reville, Eric Lee, Christopher Ly, Akshay Basi, Jessica Root, Natalia Baran, Sean M Post, Qing Deng, Hanxiao Sun, Arif O Harmanci, Jared K Burks, Javier A Gomez, Courtney D DiNardo, Naval G Daver, Gheath Alatrash, Marina Konopleva, Michael R Green, Dinler A Antunes, Andrew Futreal, Dapeng Hao, Hussein A Abbas.
      Comprehensive investigation of CD8+ T cells in acute myeloid leukemia (AML) is essential for developing immunotherapeutic strategies beyond immune checkpoint blockade. Herein, we performed single-cell RNA profiling of CD8+ T cells from 3 healthy bone marrow donors and 23 newly diagnosed (NewlyDx) and 8 relapsed/refractory (RelRef) AML patients. Cells co-expressing canonical exhaustion markers formed a cluster constituting <1% of all CD8+ T cells. We identified two effector CD8+ T cell subsets characterized by distinct cytokine and metabolic profiles that were differentially enriched in NewlyDx and RelRef patients. We refined a 25-gene CD8-derived signature correlating with therapy resistance, including genes associated with activation, chemoresistance, and terminal differentiation. Pseudotemporal trajectory analysis supported enrichment of a terminally differentiated state in CD8+ T cells with high CD8-derived signature expression at relapse or refractory disease. Higher expression of the 25-gene CD8 AML signature correlated with poorer outcomes in previously untreated AML patients, suggesting that the bona fide state of CD8+ T cells and their degree of differentiation are clinically relevant. Immune clonotype tracking revealed more phenotypic transitions in CD8 clonotypes in NewlyDx than in RelRef patients. Furthermore, CD8+ T cells from RelRef patients had a higher degree of clonal hyperexpansion associated with terminal differentiation and higher CD8-derived signature expression. Clonotype-derived antigen prediction revealed that most previously unreported clonotypes were patient-specific, suggesting significant heterogeneity in AML immunogenicity. Thus, immunologic reconstitution in AML is likely to be most successful at earlier disease stages when CD8+ T cells are less differentiated and have greater capacity for clonotype transitions.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-22-0961
  12. Clin Transl Oncol. 2023 May 11.
    Real-world genomic profiling of acute myeloid leukemia and the impact of European LeukemiaNet risk stratification 2022 update.
    Susana Elaine Alves da Rosa, Larissa Barbosa de Lima, Caroline Nunes Silveira, Luiz Gustavo Ferreira Cortes, João Bosco de Oliveira Filho, Rodrigo de Souza Reis, Murilo Castro Cervato, Pedro Henrique Sebe Rodrigues, Karla de Oliveira Pelegrino, Roberta Cardoso Petroni, Erica da Silva Araujo, Paulo Vidal Campregher.
       BACKGROUND: Acute myeloid leukemia (AML) is a myeloid neoplasm associated with a high morbidity and mortality. The diagnosis, risk stratification and therapy selection in AML have changed substantially in the last decade with the progressive incorporation of clinically relevant molecular markers.
    METHODS: In this work, our aim was to describe a real-world genomic profiling experience in AML and to demonstrate the impact of the European Leukemia Net 2022 update on risk stratification in AML.
    RESULTS AND DISCUSSION: One hundred and forty-one patients were evaluated with an amplicon-based multi-gene next-generation sequencing (NGS) panel. The most commonly mutated genes were FLT3, DNMT3A, RUNX1, IDH2, NPM1, ASXL1, SRSF2, NRAS, TP53 and TET2. Detection of FLT3 ITD with NGS had a sensitivity of 96.3% when compared to capillary electrophoresis. According to ELN 2017, 26.6%, 20.1%, and 53.3% of patients were classified as having a good, moderate, or unfavorable risk. When ELN 2022 was used, 15.6%, 27.8%, and 56.6% of patients were classified as favorable, moderate, or unfavorable risk, respectively. When ELN 2022 was compared to ELN 2017, thirteen patients (14.4%) exhibited a different risk classification, with a significant decrease in the number of favorable risk patients, what has immediate clinical impact.
    CONCLUSIONS: In conclusion, we have described a real-world genomic profiling experience in AML and the impact of the 2022 ELN update on risk stratification.
    Keywords:  Acute myeloid leukemia; Genetics
    DOI:  https://doi.org/10.1007/s12094-023-03195-5
  13. Blood. 2023 May 11. 141(19): 2293-2295
    Targeting leukemia with a metabolic genotoxin.
    Meng Wang.
      
    DOI:  https://doi.org/10.1182/blood.2022019509
  14. Leukemia. 2023 May 09.
    Mast cell deficiency prevents BCR::ABL1 induced splenomegaly and cytokine elevation in a CML mouse model.
    Melanie Langhammer, Julia Schöpf, Timo Jaquet, Katharina Horn, Moritz Angel, Corinna Spohr, Daniel Christen, Franziska Maria Uhl, Tiago Maié, Henrike Jacobi, Thorsten B Feyerabend, Julia Huber, Marcus Panning, Cassian Sitaru, Ivan Costa, Robert Zeiser, Konrad Aumann, Heiko Becker, Till Braunschweig, Steffen Koschmieder, Khalid Shoumariyeh, Michael Huber, Mirle Schemionek-Reinders, Tilman Brummer, Sebastian Halbach.
      The persistence of leukemic stem cells (LSCs) represents a problem in the therapy of chronic myeloid leukemia (CML). Hence, it is of utmost importance to explore the underlying mechanisms to develop new therapeutic approaches to cure CML. Using the genetically engineered ScltTA/TRE-BCR::ABL1 mouse model for chronic phase CML, we previously demonstrated that the loss of the docking protein GAB2 counteracts the infiltration of mast cells (MCs) in the bone marrow (BM) of BCR::ABL1 positive mice. Here, we show for the first time that BCR::ABL1 drives the cytokine independent expansion of BM derived MCs and sensitizes them for FcεRI triggered degranulation. Importantly, we demonstrate that genetic mast cell deficiency conferred by the Cpa3Cre allele prevents BCR::ABL1 induced splenomegaly and impairs the production of pro-inflammatory cytokines. Furthermore, we show in CML patients that splenomegaly is associated with high BM MC counts and that upregulation of pro-inflammatory cytokines in patient serum samples correlates with tryptase levels. Finally, MC-associated transcripts were elevated in human CML BM samples. Thus, our study identifies MCs as essential contributors to disease progression and suggests considering them as an additional target in CML therapy. Mast cells play a key role in the pro-inflammatory tumor microenvironment of the bone marrow. Shown is a cartoon summarizing our results from the mouse model. BCR::ABL1 transformed MCs, as part of the malignant clone, are essential for the elevation of pro-inflammatory cytokines, known to be important in disease initiation and progression.
    DOI:  https://doi.org/10.1038/s41375-023-01916-x
  15. Hemasphere. 2023 May;7(5): e885
    Impact of Clonal Architecture on Clinical Course and Prognosis in Patients With Myeloproliferative Neoplasms.
    Damien Luque Paz, Michael S Bader, Ronny Nienhold, Shivam Rai, Tiago Almeida Fonseca, Jan Stetka, Hui Hao-Shen, Gabriele Mild-Schneider, Jakob R Passweg, Radek C Skoda.
      Myeloproliferative neoplasms (MPNs) are caused by a somatic gain-of-function mutation in 1 of the 3 disease driver genes JAK2, MPL, or CALR. About half of the MPNs patients also carry additional somatic mutations that modify the clinical course. The order of acquisition of these gene mutations has been proposed to influence the phenotype and evolution of the disease. We studied 50 JAK2-V617F-positive MPN patients who carried at least 1 additional somatic mutation and determined the clonal architecture of their hematopoiesis by sequencing DNA from single-cell-derived colonies. In 22 of these patients, the same blood samples were also studied for comparison by Tapestri single-cell DNA sequencing (scDNAseq). The clonal architectures derived by the 2 methods showed good overall concordance. scDNAseq showed higher sensitivity for mutations with low variant allele fraction, but had more difficulties distinguishing between heterozygous and homozygous mutations. By unsupervised analysis of clonal architecture data from all 50 MPN patients, we defined 4 distinct clusters. Cluster 4, characterized by more complex subclonal structure correlated with reduced overall survival, independent of the MPN subtype, presence of high molecular risk mutations, or the age at diagnosis. Cluster 1 was characterized by additional mutations residing in clones separated from the JAK2-V617F clone. The correlation with overall survival improved when mutation in such separated clones were not counted. Our results show that scDNAseq can reliably decipher the clonal architecture and can be used to refine the molecular prognostic stratification that until now was primarily based on the clinical and laboratory parameters.
    DOI:  https://doi.org/10.1097/HS9.0000000000000885
  16. Blood Adv. 2023 May 12. pii: bloodadvances.2022007059. [Epub ahead of print]
    CD38 as a pan-hematologic target for chimeric antigen receptor T cells.
    Tina Glisovic-Aplenc, Caroline Diorio, John A Chukinas, Kimberly Veliz, Olga Shestova, Feng Shen, Selene Nunez-Cruz, Tiffaney L Vincent, Fei Miao, Michael C Milone, Carl H June, David T Teachey, Sarah K Tasian, Richard Aplenc, Saar I Gill.
      Many patients with hematologic malignancies are not curable with chemotherapy and require novel therapeutic approaches. Chimeric antigen receptor (CAR) T cell therapy is one such approach that involves the transfer of T cells engineered to express CARs for a specific cell-surface antigen. CD38 is a validated tumor antigen in multiple myeloma (MM) and in T-cell acute lymphoblastic leukemia (T-ALL) and is also overexpressed in acute myeloid leukemia (AML). Here, we developed human CD38-redirected T cells (CART-38) as a unified approach to treat three different hematologic malignancies that occur across the pediatric-to-adult age spectrum. Importantly, CD38 expression on activated T cells did not impair CART-38 cells expansion or in vitro function. In xenografted mice, CART-38-mediated rejection of AML, T-ALL, and MM cell lines and primary samples and prolonged survival. In a xenograft model of normal human hematopoiesis, CART-38 resulted in the expected reduction of hematopoietic progenitors, which warrants caution and careful monitoring of this potential toxicity when translating this new immunotherapy into the clinic. Deploying CART-38 against multiple CD38-expressing malignancies is significant, as it expands the potential for this novel therapy to impact diverse patient populations.
    DOI:  https://doi.org/10.1182/bloodadvances.2022007059
  17. Eur J Haematol. 2023 May 10.
    Impact of secondary-type mutations in NPM1 mutated AML.
    Qianghua Zhou, Davidson Zhao, Mojgan Zarif, Yu Wing Tony Yeung, Guillaume Richard-Carpentier, Hong Chang.
      
    DOI:  https://doi.org/10.1111/ejh.13979
  18. Blood. 2023 May 12. pii: blood.2022017813. [Epub ahead of print]
    The orally bioavailable GSPT1/2 degrader SJ6986 exhibits in vivo efficacy in acute lymphoblastic leukemia.
    Yunchao Chang, Fatemeh Keramatnia, Pankaj S Ghate, Gisele Nishiguchi, Qingsong Gao, Ilaria Iacobucci, Lei Yang, Divyabharathi Chepyala, Ashutosh Mishra, Anthony Andrew High, Hiroaki Goto, Koshi Akahane, Junmin Peng, Jun J Yang, Marcus Fischer, Zoran Rankovic, Charles G Mullighan.
      Advancing cure rates for high-risk acute lymphoblastic leukemia (ALL) has been limited by the lack of agents that effectively kill leukemic cells sparing normal hematopoietic tissue. Molecular glues direct the cellular ubiquitin ligase cellular machinery to target neosubstrates for protein degradation. We developed a novel Cereblon modulator, SJ6986 that exhibited potent and selective degradation of GSPT1 and GSPT2, and cytotoxic activity against childhood cancer cell lines. Here we report in vitro and in vivo testing of the activity of this agent in a panel of ALL cell lines and xenografts. SJ6986 exhibited similar cytotoxicity to the previously described GSPT1 degrader CC-90009 in a panel of leukemia cell lines in vitro, resulting in apoptosis and perturbation of cell cycle progression. SJ6986 was more effective than CC-90009 in suppressing leukemic cell growth in vivo, partly attributable to favorable pharmacokinetic properties, and did not significantly impair differentiation of human CD34+ cells ex vivo. Genome wide CRISPR/Cas9 screening of ALL cell lines treated with SJ6986 confirmed components of the CRL4CRBN complex, associated adaptors, regulators and effectors were integral in mediating the action of SJ6986. SJ6986 is a potent, selective, orally bioavailable GSPT1/2 degrader that shows broad antileukemic activity and has potential for clinical development.
    DOI:  https://doi.org/10.1182/blood.2022017813
  19. Bone Marrow Transplant. 2023 May 09.
    Second haploidentical stem cell transplantation (HAPLO-SCT2) after relapse from a first HAPLO-SCT in acute leukaemia-a study on behalf of the Acute Leukaemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT).
    Giuliano Filippini Velázquez, Myriam Labopin, Johanna Tischer, Anna Maria Raiola, Emanuele Angelucci, Alexander D Kulagin, Piero Galieni, Arancha Bermúdez, Claude-Eric Bulabois, Nicolaus Kröger, José Luis Díez-Martín, Mi Kwon, Arnon Nagler, Christoph Schmid, Fabio Ciceri, Mohamad Mohty.
      For patients with acute myeloid and lymphoblastic leukaemia (AML/ALL) lacking a matched sibling or unrelated donor, haploidentical stem cell transplantation (HAPLO-SCT) is increasingly used. However, available data on the treatment of relapse after HAPLO-SCT, including feasibility and efficacy of a second HAPLO-SCT (HAPLO-SCT2), is scarce. Hence, adults with AML/ALL, that had undergone HAPLO-SCT2 without ex-vivo manipulation after haematologic relapse from HAPLO-SCT1 were selected for a retrospective registry analysis. Eighty-two patients (AML, n = 63, ALL, n = 19, median follow-up: 33 months) were identified. Engraftment rate was 87%. At day +180, cumulative incidences of acute GvHD II-IV°/chronic GvHD were 23.9%/22.6%, respectively. Two-year overall survival/leukaemia-free survival (OS/LFS) were 34.3%/25.4%; 2-year non-relapse mortality (NRM) and relapse incidence (RI) were 17.6% and 57%. Leukaemia was the most frequent cause of death. Separated by disease, 2-year OS/LFS/NRM/RI were 28.7%/22.3%/16.2%/61.6% in AML, and 55.3%/38.4%/23.5%/38.2% in ALL patients. In a risk-factor analysis among patients with AML, stage at HAPLO-SCT1 and HAPLO-SCT2, and interval from HAPLO-SCT1 to relapse significantly influenced outcome. Our data demonstrate that HAPLO-SCT2 is a viable option in acute leukaemia relapse after HAPLO-SCT1. Engraftment, toxicity, risk factors and long-term outcome are comparable to data reported after allo-SCT2 in a matched donor setting.
    DOI:  https://doi.org/10.1038/s41409-023-01985-7
  20. FEBS J. 2023 May 12.
    Metformin exerts antileukemic effects by modulating lactate metabolism and overcomes imatinib resistance in chronic myeloid leukemia.
    Meher Bolisetti Gayatri, Rama Krishna Kancha, Dorababu Patchva, Nagaraju Velugonda, Sadasivudu Gundeti, Aramati Bm Reddy.
      Imatinib is the frontline treatment option in treating chronic myeloid leukemia (CML). Hitherto, some patients relapse following treatment. Biochemical analysis of a panel of clonally derived imatinib-resistant cells revealed enhanced glucose uptake and ATP production, suggesting increased rates of glycolysis. Interestingly, increased lactate export was also observed in imatinib-resistant cell lines. Here, we show that metformin inhibits the growth of imatinib-resistant cell lines as well as PBMCs isolated from patients who relapsed following imatinib treatment. Metformin exerted these antiproliferative effects by inhibiting MCT1 and MCT4, leading to the inhibition of lactate export. Furthermore, glucose uptake and ATP production were also inhibited following metformin treatment due to the inhibition of GLUT1 and HK-II in an AMPK-dependent manner. Our results also confirmed that metformin-mediated inhibition of lactate export and glucose uptake occurs through the regulation of mTORC1 and HIF-1α. These results delineate the molecular mechanisms underlying metabolic reprogramming leading to secondary imatinib resistance and the potential of metformin as a therapeutic option in CML.
    Keywords:  GLUT1; HIF1-α and lactate; MCT1; MCT4; Metformin
    DOI:  https://doi.org/10.1111/febs.16818
  21. Future Oncol. 2023 May 12.
    Therapies for acute myeloid leukemia in patients ineligible for standard induction chemotherapy: a systematic review.
    Michael Heuser, Cédric Fernandez, Ole Hauch, Olga M Klibanov, Tanushree Chaudhary, Vincent Rives.
      Aim: To review clinical evidence for current and emerging treatments for patients with acute myeloid leukemia (AML) who are ineligible for first-line induction chemotherapy. Methods: A systematic literature review was performed (28 October 2021) to identify clinical outcomes including overall survival (OS), event-free survival (EFS), relapse-free survival (RFS) and adverse events (AEs). Results: Of 233 references that met prespecified criteria, 26 studies were included. Adding targeted therapies (venetoclax/ivosidenib) to hypomethylating agents (HMAs) yielded better OS hazard ratios (HRs) (0.44-0.66) and EFS HRs (0.33-0.63) compared with other agents. AEs were more frequent with combination therapies than control arms, except with ivosidenib plus azacitidine. Conclusion: Targeted therapy combined with a HMA shows the most promising results in this difficult-to-treat population.
    Keywords:  IDH1; acute myeloid leukemia; hypomethylating agents; immunotherapy; ivosidenib; low-dose cytarabine; non-intensive chemotherapy; systematic literature review; targeted therapy; venetoclax
    DOI:  https://doi.org/10.2217/fon-2022-1286
  22. Blood. 2023 May 11. 141(19): 2292-2293
    Mutation signatures reveal clonal evolution.
    Yoke Seng Lee, Peter van Galen.
      
    DOI:  https://doi.org/10.1182/blood.2022019510
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