bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2025–06–08
43 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Prospective performance of the IWG-2023 criteria and IPSS-M in a phase 2 trial of guadecitabine for higher-risk MDS or CMML.
  2. Real-world outcomes of newly diagnosed AML treated with venetoclax and azacitidine or low-dose cytarabine in the UK NHS.
  3. Dasatinib overcomes AML cells resistant to BCL2 inhibition by degrading MCL1.
  4. Venetoclax and hypomethylating agents in octogenarians and nonagenarians with acute myeloid leukemia.
  5. Comparison of TP53 mutations in myelodysplasia and acute leukemia suggests divergent roles in initiation and progression.
  6. FOXP1 contributes to murine hematopoietic stem cell functionality.
  7. Bexmarilimab plus azacitidine for high-risk myelodysplastic syndrome and relapsed or refractory acute myeloid leukaemia: results from the dose-escalation part of a multicentre, single-arm, phase 1/2 trial.
  8. Serine auxotrophy is a targetable vulnerability driven by PSAT1 suppression in AML.
  9. Prospective clinical trials of venetoclax and hypomethylating agents for relapsed BPDCN.
  10. Devimistat plus chemotherapy vs chemotherapy alone for older relapsed or refractory patients with AML: results of the ARMADA trial.
  11. Sensitization of Non-M3 Acute Myeloid Leukemia Blasts to All-Trans Retinoic Acid by the LSD1 Inhibitor Tranylcypromine: TRANSATRA Phase I Study.
  12. Targetable BIRC5 dependency in therapy-resistant TP53 mutated acute myeloid leukemia.
  13. Deciphering clinical features and treatment patterns of thrombocytopenic myelodysplastic syndromes.
  14. CD302 predicts achievement of deep molecular response in patients with chronic myeloid leukemia treated with imatinib.
  15. Balancing Hematopoietic Stem Cell Self-renewal and Differentiation Activities Throughout Ontogeny and Aging.
  16. Navigating the dynamic landscape of lower-risk MDS: Advances and emerging insights.
  17. Targeting CD117 on hematopoietic stem and progenitor cells impairs CAR T cell activity.
  18. Correlation between peripheral blood and bone marrow mutations among patients with MDS from the National MDS Study.
  19. Addition of navitoclax to ruxolitinib for patients with myelofibrosis with progression or suboptimal response.
  20. Clinical correlation and prognostic impact of cytogenetic clone size for myelodysplastic syndromes/neoplasm.
  21. Therapy resistance in AML is mediated by cytoplasmic sequestration of the transcriptional repressor IRF2BP2.
  22. Targeting METTL3 protein by proteolysis-targeting chimeras: A novel therapeutic approach for acute myeloid leukemia.
  23. A phase 2 study of decitabine with or without carboplatin and arsenic trioxide in patients with MDS and AML.
  24. The Splicing Factor PTBP1 interacts with RUNX1 and is Required for Leukemia Cell Survival.
  25. Comprehensive characterization of human bone marrow microenvironment shows age-related changes.
  26. Identifying Targeted Therapies for CBFA2T3::GLIS2 Acute Myeloid Leukemia.
  27. The transcription factor HOXA9 induces expression of the chromatin modifier SMYD3 to drive leukemogenesis.
  28. Senescence and inflammation are unintended adverse consequences of CRISPR-Cas9/AAV6-mediated gene editing in hematopoietic stem cells.
  29. Treatment strategies and survival after ruxolitinib discontinuation in myelofibrosis patients: The Italian RUX-MF multicenter study.
  30. Prognostic impact of WBC kinetics after induction therapy in patients with acute myeloid leukemia (AML).
  31. Multiplex gene editing models of del(7q) reveal combined CUX1 and EZH2 loss drives clonal expansion and drug resistance.
  32. In vivo CRISPR screening identifies SAGA complex members as key regulators of hematopoiesis.
  33. Pilot Study of Low-Dose Splenic Irradiation and Transplantation in JAK Inhibitor-Refractory Myelofibrosis with Splenomegaly.
  34. A novel application of XPO1 inhibition for the treatment of myelofibrosis.
  35. Targeted Irradiation and STAT3 Inhibition Reprogram the AML Microenvironment and Extend Survival: Toward Translational Immunoradiotherapy.
  36. CoREST in pieces: Dismantling the CoREST complex for cancer therapy and beyond.
  37. Clonal composition of karyotypically normal AML at diagnosis is not affected by the microenvironment.
  38. Impact of Concomitant Azoles on Ruxolitinib Treatment in Patients With GVHD: Post Hoc Analyses of REACH2 and REACH3.
  39. Competition of dual SF3B1 mt clones in MDS-RS is associated with distinct RNA mis-splicing in hematopoietic stem cells.
  40. Adult thymectomy is associated with increased mortality risk from cancer but not cardiovascular disease.
  41. A feedforward loop between ACLY and MYC supports T-ALL progression in vivo.
  42. Cheminformatic identification of small molecules targeting acute myeloid leukemia.
  43. Instructive interaction between myelodysplastic hematopoiesis and the bone marrow microenvironment at the single-cell level.
  1. Blood Neoplasia. 2024 Jun;1(2): 100008
    Prospective performance of the IWG-2023 criteria and IPSS-M in a phase 2 trial of guadecitabine for higher-risk MDS or CMML.
    Samuel Urrutia, Prithviraj Bose, Yesid Alvarado, Gautam Borthakur, Farhad Ravandi, Naval Daver, Naveen Pemmaraju, Elias Jabbour, Koichi Takahashi, Tapan Kadia, Courtney DiNardo, Steven Kornblau, Rashmi Kanagal-Shamanna, Xuelin Huang, Kristy Bodden, Hagop Kantarjian, Guillermo Garcia-Manero.
      Guadecitabine (SGI-110) is a dinucleotide form of decitabine that has been studied in myelodysplastic syndrome (MDS) and acute myeloid leukemia. Here, we present the results of a single-center phase 2 trial of this agent for patients with higher-risk MDS or chronic myelomonocytic leukemia (CMML). Guadecitabine was administered at a dose of 60 mg/m2 subcutaneously for 5 days. Of 100 enrolled patients, 82% had MDS. The median age was 69 years, and International Prognostic Scoring System (IPSS) was intermediate-2 in 78% and high in 14%. Thirty-eight percent had complex cytogenetics, and 32% had TP53 mut . By the International Working Group 2006 (IWG-2006) criteria, 25% achieved complete remission (CR), 30% marrow CR, and 33% no response (NR). Common grade 3 events were febrile neutropenia (32%) and infection (25%). Mortality rates at 4 and 8 weeks were 0% and 4%, respectively. The median overall survival (mOS) was 16.8 months. Patients who underwent transplantation (21%) had an mOS of 46.6 months. We then reanalyzed this data set using IPSS-Molecular (IPSS-M) and IWG-2023 response criteria. By IPSS-M, 60% of patients were classified as very high and 27% as high risk. By IWG-2023, overall response rate was 52%, with 30% CR, 14% CR with limited count recovery, and 42% NR. IPSS-M provided adequate risk stratification at enrollment. Patients classified as marrow CR had widely different outcomes when reclassified by IWG-2023. In conclusion, SGI-110 was active in high-risk MDS, but survival is unlikely to be superior to current hypomethylating agents. The study is registered at www.ClinicalTrials.gov as #NCT02131597.
    DOI:  https://doi.org/10.1016/j.bneo.2024.100008
  2. Blood Neoplasia. 2024 Sep;1(3): 100017
    Real-world outcomes of newly diagnosed AML treated with venetoclax and azacitidine or low-dose cytarabine in the UK NHS.
    Jad Othman, Ho Pui Jeff Lam, Sarah Leong, Faisal Basheer, Islam Abdallah, Kathryn Fleming, Priyanka Mehta, Heba Yassin, John Laurie, Michael Austin, Paolo Gallipoli, Tom Taylor, Mike Dennis, Johnathon Elliot, Georgina Clarke, Raymond Dang, Jennifer Vidler, Pramila Krishnamurthy, Anne-Louise Latif, Pallavi Kalkur, Maryam Shahidianakbar, Victoria Campbell, Deepak Mannari, Emily Sutherland, Thishakya Wickramaratne, Angela Collins, Rui Zhao, Herng Mak, Edward Belsham, Shabnam Banerjee, Jamila Bashir, Srinivas Pillai, Richard Whitmill, Sofia Galli, Mariam Amer, Vidhya Murthy, Duncan Murray, Farooq Wandroo, Francesca Hogan, Francesca Crolla, Nicole Fowler, Anjum Khan, Jenny O'Nions, Richard Dillon.
      Venetoclax with azacitidine is the standard of care for patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy; however, uncertainties remain regarding the treatment schedule, accurate prognostication, and outcomes for patients treated outside clinical trials. The option of venetoclax with low-dose cytarabine (LDAC) is also available; however, it is not clear for which patients it may be a useful alternative. Here, we report a large real-world cohort of 654 patients treated in 53 UK hospitals with either venetoclax and azacitidine (n = 587) or LDAC (n = 67). The median age was 73 years, and 59% had de novo AML. Most patients received 100 mg of venetoclax with an azole antifungal. In cycle 1, patients spent a median of 14 days in the hospital, and 85% required red cell transfusion, 59% platelet transfusion, and 63% required IV antibiotics. Supportive care requirements significantly reduced after the first cycle. Patients receiving venetoclax-azacitidine had a complete remission (CR)/CR with incomplete hematological recovery rate of 67%, day 30 and day 60 mortality of 5% and 8%, respectively, and median overall survival of 13.6 months. Mutations in NPM1, RUNX1, STAG2, and IDH2 were associated with improved survival, whereas age, secondary and therapy-related AML, +8, MECOM rearrangements, complex karyotype, ASXL1, and KIT mutations were associated with poorer survival. Prognostic systems derived specifically for patients treated with venetoclax-azacitidine performed better than the European LeukemiaNet and Medical Research Council classifications; however, improved risk classifications are still required. In the 149 patients with NPM1 mutated AML, outcomes were similar for those treated with venetoclax-azacitidine and venetoclax-LDAC.
    DOI:  https://doi.org/10.1016/j.bneo.2024.100017
  3. Br J Haematol. 2025 Jun 06.
    Dasatinib overcomes AML cells resistant to BCL2 inhibition by degrading MCL1.
    Sylvain Garciaz, Camille Montersino, Maxence Bourgoin, Arnaud Jacquel, Rémy Castellano, Arnaud Guille, Max Chaffanet, François Bertucci, Marie-Anne Hospital, José Adélaïde, Patrick Auberger, Norbert Vey, Yves Collette.
      Acute myeloid leukaemia (AML) is a severe disease occurring mainly in the elderly population. Venetoclax (VEN) combined with azacitidine has changed the paradigm of treatment of AML. Nevertheless, approximately 30% of patients are primary refractory to VEN (VEN-R), with no current therapeutic option. To target VEN-R AML, we collected primary blasts at AML diagnosis in a prospective biobanking trial (NCT02320656). We performed targeted Next Generation Sequencing and ex vivo drug testing in 108 AML samples. We noticed that 17 (15.7%) were navitoclax-resistant (NAV-R). We observed a strong anticorrelation between NAV and Dasatinib (DASA) ex vivo sensitivity, also found in the BEAT-AML cohort. As NAV and ABT797 are both BCL2/BCLxL inhibitors, we hypothesized that blasts sensitive to DASA (DASA-S) were dependent on MCL1. We performed BH3 profiling in 25 samples confirming MCL1 dependency. Immunoblots showed a higher MCL1 and BIM protein expression. We found a dose-dependent decrease in MCL1 protein expression associated with caspase 3 activation upon DASA in a primary AML sample. Collectively, these results suggest that DASA degrades MCL1 and effectively kills AML cells. To prove this hypothesis, we designed a phase II clinical trial named VEN-R DASA-IPC 2022 067 (EUCT 2023-505846-24-00), currently enrolling VEN-R patients.
    Keywords:  acute leukaemia; apoptosis; drug resistance
    DOI:  https://doi.org/10.1111/bjh.20195
  4. Blood Neoplasia. 2024 Jun;1(2): 100016
    Venetoclax and hypomethylating agents in octogenarians and nonagenarians with acute myeloid leukemia.
    Ellen Madarang, Jillian Lykon, Wei Zhao, Mikkael A Sekeres, Terrence Bradley, Namrata S Chandhok, Justin Taylor, Sangeetha Venugopal, Tulay Koru-Sengul, Sunil Girish Iyer, Jason S Gilbert, Ryan M Miller, Jacopo Nanni, Irene Zacheo, Agnese Mattei, Najla Al Ali, Ashwin Kishtagari, Giovanni Marconi, David A Sallman, Daniel A Pollyea, Michael R Savona, Cristina Papayannidis, Rami Komrokji, Justin Watts.
      Venetoclax (VEN) plus a hypomethylating agent (HMA) regimen is the standard of care for older adults with acute myeloid leukemia (AML); however, it is associated with significant myelosuppression and complications, potentially limiting its use in those who are very old. We performed a multicenter retrospective analysis of VEN-HMA treatment in octogenarians and nonagenarians to further understand the tolerability, feasibility, dosing considerations, and clinical efficacy in this unique group. Patients with AML aged ≥80 years who received VEN-HMA between March 2015 and April 2022 were reviewed. VEN-HMA dosing was determined by treating physician, accounting for CYP3A4 drug interaction dose adjustments. In total, 154 patients were included, with a median age of 82 years (range, 80-92), who received treatment with VEN-HMA (83% with azacitidine and 17% with decitabine). Most patients (53%) had European LeukemiaNet 2017 adverse risk AML, 33% had intermediate, 8% had favorable, and 6% were unknown. With a median follow-up of 7.7 months, 36 patients (23%) remained in remission, with 31 (20%) still on VEN-HMA. The 30-day and 60-day mortality rates were 8.5% and 17%, respectively. The composite complete remission (CRc) rate for patients with newly diagnosed AML without prior myelodysplastic syndrome was 73% (48 of 66). Median overall survival (OS) was 8.1 months, and in patients who achieved a response (CRc), median OS was 13.2 months. Landmark analysis from the time CRc was first achieved showed that patients receiving VEN for ≤14 days had improved OS; median, 24.0 months. Patients who are very old can be treated safely with combination VEN-HMA with expectations of dose reductions and cycle extensions to ensure tolerability over the long term.
    DOI:  https://doi.org/10.1016/j.bneo.2024.100016
  5. Blood Neoplasia. 2024 Mar;1(1): 100004
    Comparison of TP53 mutations in myelodysplasia and acute leukemia suggests divergent roles in initiation and progression.
    Ashwini Jambhekar, Emily E Ackerman, Berk A Alpay, Galit Lahav, Scott B Lovitch.
      TP53 mutation predicts adverse prognosis in many cancers, including myeloid neoplasms, but the mechanisms by which specific mutations affect disease biology, and whether they differ between disease categories, remain unknown. We analyzed TP53 mutations in 4 myeloid neoplasm subtypes (myelodysplastic syndrome [MDS], acute myeloid leukemia [AML], AML with myelodysplasia-related changes [AML-MRC], and therapy-related AML), and identified differences in mutation types, spectrum, and hot spots between disease categories and in comparison to solid tumors. Missense mutations in the DNA-binding domain were most common across all categories, whereas inactivating mutations and mutations outside the DNA binding domain were more common in AML-MRC than in MDS. TP53 mutations in MDS were more likely to retain transcriptional activity, and comutation profiles were distinct between disease categories and mutation types. Our findings suggest that mutated TP53 contributes to initiation and progression of neoplasia via distinct mechanisms, and support the utility of specific identification of TP53 mutations in myeloid malignancies.
    DOI:  https://doi.org/10.1016/j.bneo.2024.100004
  6. Exp Hematol. 2025 May 29. pii: S0301-472X(25)00106-7. [Epub ahead of print] 104815
    FOXP1 contributes to murine hematopoietic stem cell functionality.
    Françoise Levavasseur, Samia Oussous, Alessandro Framarini, Ismael Boussaid, Panhong Gou, Zubaidan Tuerdi, Iman Litchy Boueya, Helyette Hoffner, Marta De Almeida, Morgane Le Gall, Haley Tucker, Stéphane Giraudier, Didier Bouscary, Michaela Fontenay, Diana Passaro, Isabelle Dusanter-Fourt, Evelyne Lauret.
      Transcription factor forkhead box P1 (FOXP1) is a key regulator of immune cell functions. We have shown that FOXP1 contributes to the expansion of human hematopoietic stem/progenitor (HSPC) and acute myeloid leukaemia cells. Here, we investigated the role of FOXP1 in early adult mouse hematopoiesis in vivo. We showed that loss of hematopoietic-specific FOXP1 expression leads to attrition of the HSC and multipotent progenitor (MPP)-1 compartment in parallel with enhancement of myeloid-biased MPP3 in adult bone marrow and fetal liver. Transplantation experiments confirmed that FOXP1-deficient bone marrow had an intrinsic reduced HSC compartment. FOXP1-deficient MPP compartments also showed enhanced proliferation with G0 phase reduction. Transcriptome analyses revealed that FOXP1-deficient HSC exhibited reduced stemness and enhanced expression of cell proliferation pathways. Thus, our current results reveal the important contribution of FOXP1 in early murine hematopoiesis through HSC maintenance, limited expansion of all MPP compartments and restriction of early myeloid commitment in vivo.
    DOI:  https://doi.org/10.1016/j.exphem.2025.104815
  7. Lancet Haematol. 2025 May 28. pii: S2352-3026(25)00103-6. [Epub ahead of print]
    Bexmarilimab plus azacitidine for high-risk myelodysplastic syndrome and relapsed or refractory acute myeloid leukaemia: results from the dose-escalation part of a multicentre, single-arm, phase 1/2 trial.
    Mika Kontro, Anthony Selwyn Stein, Marja Pyörälä, Johanna Rimpiläinen, Timo Siitonen, Arno Ylitalo, Marie-Louise Fjällskog, Juho Jalkanen, Sofia Aakko, Inka Pawlitzky, Maija Hollmén, Naval Daver.
       BACKGROUND: Bexmarilimab blocks Clever-1 on macrophages to enhance antigen presentation and T cell activation. Because Clever-1 is expressed by myeloid leukaemia cells, bexmarilimab may combat leukaemia and influence the tumour microenvironment to augment the effectiveness of standard-of-care therapy in patients with myelodysplastic syndrome and acute myeloid leukaemia. The aim of this study was to determine the safety of bexmarilimab in combination with standard-of-care treatment in myelodysplastic syndrome and acute myeloid leukaemia and to identify the recommended dose for expansion of bexmarilimab in combination with standard of care.
    METHODS: The phase 1 dose-escalation part of this multicentre, single-arm, phase 1/2 study was done at six centres in Finland and the USA. Patients aged 18 years or older (Eastern Cooperative Oncology Group performance status of 2 or less) with myelodysplastic syndrome (2016 WHO) with a Revised International Prognostic Scoring System (IPPS-R) score of 3·5 or more for USA (3·0 for the European Union), chronic myelomonocytic leukaemia (2016 WHO) with 10-19% marrow blasts, myelodysplastic syndrome or chronic myelomonocytic leukaemia with no response to or disease progression during hypomethylating agent treatment, or relapsed or refractory acute myeloid leukaemia were treated with escalating doses of bexmarilimab (1·0 mg/kg, 3·0 mg/kg, and 6·0 mg/kg, intravenous, once weekly, 28-day cycle) in combination with azacitidine, administered as per label. Here we report the phase 1 part of the study, for which the primary outcome was safety (the incidence and frequency of dose limiting toxicities and the frequency and severity of adverse events) as well as the determination of the maximum tolerated dose and recommended expansion dose for the phase 2 part using a Bayesian optimal interval design. All patients receiving at least one dose of bexmarilimab were included in safety analyses, and those with a post-baseline activity assessment were included in activity analyses. This trial is registered with ClinicalTrials.gov (NCT05428969) and EudraCT (2021-002104-12) databases. Phase 2 of the study is ongoing in patients with myelodysplastic syndrome with no response to hypomethylating agent.
    FINDINGS: Between June 2, 2022, and Dec 7, 2023, 33 patients (14 with myelodysplastic syndrome, 19 with relapsed or refractory acute myeloid leukaemia) were enrolled in phase 1; no patients with chronic myelomonocytic leukaemia were identified. 19 (58%) patients were male and 14 (42%) were female, and 24 (73%) patients were non-Hispanic ethnicity, and eight (24%) were White. Median follow-up time for all patients was 6·2 months (IQR 3·5-10·7). The maximum tolerated dose was not reached, and the recommended expansion dose for phase 2 was established as 6·0 mg/kg in patients with myelodysplastic syndrome with no response to hypomethylating agents. There were no dose-limiting toxicities. The most common grade 3-4 treatment-emergent adverse events were febrile neutropenia (n=8 [24%]), anemia (n=7 [21%]), and thrombocytopenia (n=5 [15%]). Treatment-emergent deaths occurred as a result of sepsis (n=1 [3%]), neutropenic infection (n=1 [3%]), and haemophagocytic lymphohistiocytosis (n=1 [3%]). Four patients presented treatment-related serious adverse events, one patient in the 1·0 mg/kg group, two in the 3·0 mg/kg group and one in the 6·0 mg/kg group. These included rash (grade 3), capillary leak syndrome (grade 3), cryptogenic organising pneumonia (grade 3) and haemophagocytic lymphohistiocytosis (grade 5) which led to one death. The objective response rate was 45% (15 of 33; 95% CI 28-62) across all doses.
    INTERPRETATION: Bexmarilimab in combination with azacitidine has a manageable safety profile, consistent with azacitidine, and shows promising clinical activity in patients with high-risk myelodysplastic syndrome.
    FUNDING: Faron Pharmaceuticals.
    DOI:  https://doi.org/10.1016/S2352-3026(25)00103-6
  8. bioRxiv. 2025 May 14. pii: 2025.05.13.651470. [Epub ahead of print]
    Serine auxotrophy is a targetable vulnerability driven by PSAT1 suppression in AML.
    Ilias Sinanidis, Panagiotis Tsakiroglou, Benjamin Dubner, Rebecca Foertsch, Julia Gondek, InYoung Choi, Bogdan Paun, Liang Zhao, Gabriel Ghiaur, W Brian Dalton.
      Serine metabolism is of growing biologic and therapeutic interest in cancer. Upregulation of the serine synthesis pathway (SSP) can fuel tumor growth, and cancers with this phenotype are often sensitive to SSP inhibitors. In parallel, dietary restriction of serine and glycine (SG) can suppress some cancers, but the determinants of sensitivity to this approach are poorly understood. This is especially true in acute myeloid leukemia (AML), where serine metabolism has been less explored. We report that a subset of human AML cell lines and primary samples are completely dependent on external serine, known as serine auxotrophy. These leukemias consistently suppressed the SSP enzyme PSAT1, failed to synthesize serine, responded to SG restriction in vivo , and were rescued by restoring PSAT1. We also found that AML with an SF3B1 K700E mutation showed additional dependence on the SSP enzyme PHGDH, that SG restriction synergized with venetoclax in serine auxotrophic AML, and that MECOM rearrangement was strongly associated with PSAT1 suppression and serine auxotrophy. These findings define a metabolically distinct AML subtype and nominate it for targeting by SG restriction.
    DOI:  https://doi.org/10.1101/2025.05.13.651470
  9. Blood Neoplasia. 2025 May;2(2): 100086
    Prospective clinical trials of venetoclax and hypomethylating agents for relapsed BPDCN.
    Naveen Pemmaraju, Luan Hai Phan, Geoffrey Fell, Marlise R Luskin, Mahesh Swaminathan, Sherry Pierce, Courtney DiNardo, Abhishek Maiti, Marina Konopleva, Andrew A Lane.
      
    DOI:  https://doi.org/10.1016/j.bneo.2025.100086
  10. Blood Neoplasia. 2024 Jun;1(2): 100009
    Devimistat plus chemotherapy vs chemotherapy alone for older relapsed or refractory patients with AML: results of the ARMADA trial.
    Timothy S Pardee, Bayard L Powell, Richard A Larson, Joseph Maly, Michael Keng, Matthew Foster, Eun-Ji Choi, Heinz Sill, Thomas Cluzeau, Deepa Jeyakumar, Olga Frankfurt, Prapti Patel, Michael Schuster, Elisabeth Koller, Regis Costello, Uwe Platzbecker, Pau Montesinos, Susana Vives, Aziz Nazha, Rachel Cook, Carlos Vigil-Gonzales, Sylvain Chantepie, Sanjeev Luther, Jorge Cortes.
      Acute myeloid leukemia (AML) is an aggressive cancer of the myeloid lineage. Outcomes in older patients are poor, with high rates of resistant and relapsed disease. Devimistat is a lipoic acid analog that inhibits mitochondrial metabolism. Devimistat combined with high-dose cytarabine and mitoxantrone resulted in promising phase 1 and 2 response rates especially in older patients. Therefore, the phase 3 ARMADA 2000 trial was conducted in patients aged ≥50 years with relapsed or refractory AML. The study randomized patients between devimistat combined with high-dose cytarabine and mitoxantrone (CHAM) or 1 of 3 control treatment regimens without devimistat: high-dose cytarabine and mitoxantrone; mitoxantrone, etoposide, and cytarabine; or fludarabine, cytarabine, and filgrastim. Overall, 265 patients consented to participate from 56 sites across 11 countries, and 200 patients were randomized, 98 patients to the devimistat arm and 102 patients to the control arm. The safety profile was consistent with high-dose cytarabine-based salvage regimens. There were 18 (9%) deaths on study (11 on CHAM and 7 on control). The study failed to meet its primary end point, with a complete remission (CR) rate of 20.4% in the devimistat arm compared with 21.6% in the control arm (P = .57). Overall survival was not statistically significantly different between the study arms, with a median of 8.9 months in the CHAM arm compared with 6.2 months in the control arm (P = .62). In conclusion, devimistat added to chemotherapy did not improve the CR rate or survival in patients aged ≥50 years with relapsed or refractory AML. This trial was registered at www.ClinicalTrials.gov as #NCT03504410.
    DOI:  https://doi.org/10.1016/j.bneo.2024.100009
  11. Eur J Haematol. 2025 Jun 03.
    Sensitization of Non-M3 Acute Myeloid Leukemia Blasts to All-Trans Retinoic Acid by the LSD1 Inhibitor Tranylcypromine: TRANSATRA Phase I Study.
    Michael Kruszewski, Claudia Schmoor, Tobias Berg, Usama-Ur Rehman, Marcus Schittenhelm, Katharina Götze, Andrea Kündgen, Caroline Pabst, Tobias Ma, Anna Frey, Julia Stomper, Dietmar Pfeifer, Eric Metzger, Johannes Jung, Kevin Moschallski, Johanna Thomas, Gesine Bug, Justus Duyster, Manfred Jung, Roland Schüle, Ralph Wäsch, Olga Grishina, Michael Lübbert.
      The treatment of elderly, nonfit acute myeloid leukemia (AML)/MDS patients with relapsed/refractory (R/R) disease remains challenging. As histone demethylase LSD1 (KDM1A) is a rational therapeutic target in AML, we conducted a phase I trial ("rolling-six design") with the LSD1 inhibitor tranylcypromine (TCP, dose levels [DL] 20, 40, 60, 80 mg p.o. d1-28) combined with fixed-dose ATRA (45 mg/m2 p.o. d10-28) and low-dose cytarabine (LDAC, 40 mg s.c. d1-10). The primary endpoint was dose-limiting toxicity (DLT) in the first 28 days of treatment. The aim was the determination of the maximum tolerated TCP dose (MTD). Twenty-three patients with AML and 2 with MDS were accrued. TCP was administered for a median of 39.5 days (range: 11-228). No DLTs were observed at any DL; MTD could not be established. No differentiation syndrome occurred. Two patients attained a PR; SD was achieved in 10 of 22 evaluable patients. Median OS was 62 days (range: 14-325). Accompanying studies included pharmacokinetics, serial determinations of fetal hemoglobin (HbF), detection of CD38 upregulation with treatment, as well as transcriptome changes in purified blood blasts over time. In conclusion, the combination of TCP with ATRA and LDAC was well feasible, even at the highest DL. Hence, studies with more potent LSD1 inhibitors appear warranted. Trial Registration: German Clinical Trials Register (DRKS): DRKS00006055. For further Information see https://drks.de/search/en/trial/DRKS00006055.
    Keywords:  CD38; LSD1; chromatin; differentiation; histone demethylase; myelodysplastic syndrome
    DOI:  https://doi.org/10.1111/ejh.14426
  12. bioRxiv. 2025 May 22. pii: 2025.05.17.654633. [Epub ahead of print]
    Targetable BIRC5 dependency in therapy-resistant TP53 mutated acute myeloid leukemia.
    Ahmed M Mamdouh, Fang Qi Lim, Yang Mi, Elyse A Olesinski, Cheryl Gek Teng Chan, Shaista Jasdanwala, Xiao Xian Lin, Yichen Wang, Jordan Yong Ming Tan, Karanpreet Singh Bhatia, Valeriia Sapozhnikova, Chuqi Wang, Aarthi Nivasini Mahesh, Daniel Tan En Liang, Nishtha Chitkara, Philipp Mertins, Leah Hogdal, Brandon D Brown, Torsten Haferlach, Camille Lobry, Coleman Lindsley, Alexandre Puissant, Han Kiat Ho, Sanjukta Das, Anthony Letai, Steven M Kornblau, Jan Krönke, Edward Ayoub, Koji Itahana, Michael Andreeff, Shruti Bhatt.
      TP53 mutations confer treatment resistance across multiple cancers. Mechanisms of therapy resistance, beyond affecting transactivation of BCL-2 family genes, remain a mystery. Here, we report that TP53 mutated AML, triple negative breast cancer, and colorectal cancer escape therapy-induced apoptosis due to inability to activate caspase-3/7, despite having normal mitochondrial outer membrane permeabilization (MOMP) induction. To identify post-MOMP determinants of therapy resistance in TP53 mutated AML, we applied a multiomics approach - whole-genome CRISPR screen, bulk/single-cell RNAseq, and high-throughput drug screen. BIRC5 , encoding survivin, was selectively upregulated in paired hematopoietic stem/multipotent progenitor cells from TP53 mutant AML patients, with further enrichment after venetoclax-azacitidine (VenAza) relapse. Critically, BIRC5 was also upregulated in 17 of 26 TP53 mutant TCGA cancers. Genetic ablation of BIRC5 resensitized TP53 mutated AML to standard therapy by restoring caspase activation, validating therapeutic relevance. Importantly, targeting IAPs and survivin using clinically relevant inhibitors overcame VenAza resistance of TP53 mutant tumors in vivo , achieving sustained AML suppression. Combination with survivin inhibitors also overcame chemotherapy resistance in TP53 deficient solid cancers. Together, we discovered that wild-type TP53 is required in post-MOMP signaling and that BIRC5 dependency is an effective therapeutic target for poor prognosis, TP53 mutated cancers.
    DOI:  https://doi.org/10.1101/2025.05.17.654633
  13. Ann Hematol. 2025 Jun 05.
    Deciphering clinical features and treatment patterns of thrombocytopenic myelodysplastic syndromes.
    Nicole Galli, Loredana Pettine, Giorgio Croci, Francesco Passamonti, Wilma Barcellini, Bruno Fattizzo.
      Here we studied 260 patients with myelodysplastic neoplasms (MDS) focusing on thrombocytopenic patients with PLT < 50 × 109/L. Clinical and laboratory features, bone marrow data, therapies and outcomes were compared with MDS without thrombocytopenia. Thirty-five subjects (13.5%) had moderate to severe thrombocytopenia (median PLT 38 × 109/L, range: 9-50 × 109/L) and 20% displayed signs of bleeding, mostly grade 1-2. At diagnosis, thrombocytopenic MDS were mostly low- or very low- risk IPSS-R, a higher frequency of 40% belonged to intermediate IPSS-R group. Bone marrow evaluation showed hypocellularity (26% vs. 8.4%) and abnormal karyotype (46% vs. 27%), with trisomy 8 and complex karyotype as the most frequent alterations. Eighteen patients (51%) underwent NGS for genes commonly mutated in myeloid neoplasms, detecting at least a mutation in 11 (61%), with TP53 and STAG2 as most frequent. In a subgroup analysis immune-histochemistry on bone marrow biopsies highlighted deposits of IgG, IgM, and complement fractions C3 and C4d in most cases. AML transformation and mortality rates were superior in thrombocytopenic versus non-thrombocytopenic patients. Two distinct phenotypes of thrombocytopenic MDS could be hypothesized, one closer to immune thrombocytopenia marked by trisomy 8 and STAG2 mutation, responsive to immunosuppressive treatment and the other more similar to higher-risk MDS with complex karyotypes and TP53 mutations showing a worsen outcome.
    Keywords:  Autoimmunity; Myelodysplastic syndromes; NGS; Thrombocytopenia; Trephine biopsy
    DOI:  https://doi.org/10.1007/s00277-025-06421-y
  14. Blood Neoplasia. 2024 Jun;1(2): 100014
    CD302 predicts achievement of deep molecular response in patients with chronic myeloid leukemia treated with imatinib.
    Chung Hoow Kok, Yazad Irani, Jade Clarson, Verity Saunders, Phuong Dang, Naranie Shanmuganathan, Susan Branford, David Yeung, Agnes S M Yong, Timothy P Hughes.
      Achieving a deep molecular response (DMR) is a prerequisite for treatment-free remission in chronic myeloid leukemia (CML) and a key milestone for patients with CML. This study identified patients unlikely to achieve a 5-year DMR through differential expression of cluster of differentiation (CD) genes, and clinical variables at diagnosis. Peripheral blood samples (n = 131) from patients treated with imatinib or nilotinib underwent transcriptomic microarray profiling. The decision-tree analysis delineated 2 distinct poor-risk (PR) cohorts, distinguished by high 3-month BCR::ABL1% (PR-1), or high CD302 expression (PR-2). The 5-years DMR achievement rate was significantly lower in both PR groups than in the good-risk (GR) group in patients treated frontline with imatinib (0% vs 27% vs 83%; P < .0001) or nilotinib (PR-2 vs GR, 17% vs 83%; P = .02). Gene-set enrichment analysis revealed reduced expression of cell cycle-related genes in PR-2, as well as increased metabolism and STAT3 pathway genes, which has previously been linked to leukemic cell persistence and resistance to tyrosine kinase inhibitors. Moreover, PR-2 had a higher frequency of CD34+CD302+ and CD14+CD302+ cells than GR samples. Strategies aimed at targeting STAT3 and/or metabolic pathways associated with high CD302 may provide novel therapeutic approaches that could help improve treatment outcomes and eradicate residual disease.
    DOI:  https://doi.org/10.1016/j.bneo.2024.100014
  15. Exp Hematol. 2025 May 31. pii: S0301-472X(25)00111-0. [Epub ahead of print] 104820
    Balancing Hematopoietic Stem Cell Self-renewal and Differentiation Activities Throughout Ontogeny and Aging.
    Masayuki Yamashita, Jingjing Li, Vu L Tran, Myriam L R Haltalli, Shannon McKinney-Freeman, Toshio Suda.
      During fetal development, lifelong hematopoietic stem cells (HSCs) emerge from hemogenic endothelium as a part of the intra-arterial hematopoietic clusters. These definitive HSCs are deemed to colonize and expand in the fetal liver, migrate to the bone marrow, and produce mature blood cells throughout life. However, emerging lines of evidence have challenged this paradigm, and alternative models have been proposed. Moreover, recent studies have revealed expansion of HSCs during aging, which seems counterintuitive to their age-dependent reduction in regenerative capacity. Here, we summarize emerging views on hematopoietic ontogeny and aging, which was the focus of the Summer 2024 International Society for Experimental Hematology (ISEH) webinar. Teaser Abstract: During fetal development, lifelong hematopoietic stem cells (HSCs) emerge from hemogenic endothelium as a part of the intra-arterial hematopoietic clusters. These definitive HSCs are deemed to colonize and expand in the fetal liver, migrate to the bone marrow, and produce mature blood cells throughout life. However, emerging lines of evidence have challenged this paradigm, and alternative models have been proposed. Moreover, recent studies have revealed expansion of HSCs during aging, which seems counterintuitive to their age-dependent reduction in regenerative capacity. Here, we summarize emerging views on hematopoietic ontogeny and aging.
    Keywords:  Hematopoietic stem cells; differentiation; fetal liver; lineage tracing; mitochondrial metabolism; self-renewal
    DOI:  https://doi.org/10.1016/j.exphem.2025.104820
  16. Blood Rev. 2025 May 14. pii: S0268-960X(25)00046-3. [Epub ahead of print] 101301
    Navigating the dynamic landscape of lower-risk MDS: Advances and emerging insights.
    Alain Mina, Yazan Madanat, Yasmin Abaza, Amer M Zeidan.
      Myelodysplastic syndromes/neoplasms (MDS) are a group of clonal myeloid malignancies characterized by ineffective hematopoiesis, cytopenias, and an increased risk of transformation to acute myeloid leukemia (AML). In lower-risk (LR) MDS, as defined by the revised and molecular international prognostic scoring systems (IPSS-R and IPSS-M), anemia is often the predominant clinical manifestation. Treatment strategies have traditionally focused on supportive care, including transfusion support and erythropoiesis stimulating agents (ESAs). While allogeneic hematopoietic stem cell transplantation remains the only potentially curative option for select patients, LR-MDS remain otherwise incurable with current therapies. With the exception of lenalidomide which was approved in 2005 in USA, therapeutic advancements in LR-MDS have stalled for almost 15 years. Progress has been limited by the disease's inherent complexity, indolent nature, and significant heterogeneity, as well as challenges in clinical trial design and execution. Recent advances in gene sequencing and molecular analyses have significantly increased our understanding of disease biology. These insights, coupled with collaborative efforts across the academic community, have led to meaningful shifts in classification, prognostication, and response assessment paradigms in LR-MDS. This evolution has led to a number of approvals, including luspatercept approved in 2020, and imetelstat, which was approved in 2024 in USA. As the therapeutic landscape of LR-MDS continues to evolve, there is growing optimism that these recent milestones will pave the way for further advancements and improved patient outcomes. Next set of studies should focus on the optimal sequencing and combinations of existing agents, as well as moving forward novel effective agents.
    Keywords:  ICC; IPSS-M; Lower-risk; Myelodysplastic syndromes; Novel therapies; WHO
    DOI:  https://doi.org/10.1016/j.blre.2025.101301
  17. Mol Ther. 2025 May 30. pii: S1525-0016(25)00403-4. [Epub ahead of print]
    Targeting CD117 on hematopoietic stem and progenitor cells impairs CAR T cell activity.
    Rubina Thomas, Julie K Ritchey, John F DiPersio, Miriam Y Kim.
      CD117 is a cell surface receptor expressed on hematopoietic stem and progenitor cells (HSPCs) and acute myeloid leukemia (AML), and thus CD117-targeting CAR T cells (CART117) can function as both conditioning for hematopoietic stem cell transplant (HSCT) and a therapy for AML. We developed human and mouse CART117 to evaluate the safety and feasibility of targeting CD117 in preclinical mouse models. Human CART117 had potent anti-tumor activity while also mediating significant hematopoietic toxicity in a humanized mouse model. Murine CART117 (mCART117) led to systemic and hematopoietic toxicity without anti-leukemic benefit in immunocompetent C57BL/6 mice. Intriguingly, mCART117 was able to eliminate CD117+ cells in the spleen but not in the BM. Of note, proliferation of BM CD117+ cells in response to lymphodepleting chemotherapy amplified mCART117-mediated systemic toxicity. Alternative lymphodepletion with radiation ameliorated the systemic toxicity of mCART117 but did not improve anti-leukemic efficacy. Immunodeficient mice given mCART117 in the absence of lymphodepletion died from severe pancytopenia, and this effect was recapitulated by Treg depletion in immunocompetent mice. Increasing CD117 expression on AML improved the anti-leukemic efficacy and toxicity profile of mCART117. In conclusion, mCART117 anti-leukemic activity is impaired in immunocompetent mice when CD117 is expressed at physiological levels on AML.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.05.033
  18. Blood Neoplasia. 2024 Sep;1(3): 100026
    Correlation between peripheral blood and bone marrow mutations among patients with MDS from the National MDS Study.
    Amy E DeZern, Johannes B Goll, Travis L Jensen, Sridhar Nonavinkere Srivatsan, Nancy K Gillis, Gregory A Abel, Eric Padron, H Joachim Deeg, Tareq Al Baghdadi, Jane Jijun Liu, Rami S Komrokji, Steven D Gore, Wael Saber, Rafael Bejar, Matthew J Walter, R Coleman Lindsley, Seth Sherman, Nancy DiFronzo, Mikkael A Sekeres.
      
    DOI:  https://doi.org/10.1016/j.bneo.2024.100026
  19. Blood Neoplasia. 2025 Feb;2(1): 100056
    Addition of navitoclax to ruxolitinib for patients with myelofibrosis with progression or suboptimal response.
    Naveen Pemmaraju, Tim C P Somervaille, Francesca Palandri, Claire Harrison, Rami S Komrokji, Andrew Perkins, Rosa M Ayala Diaz, David Lavie, Akihiro Tomita, Yang Feng, Qin Qin, Jason Harb, Akshanth R Polepally, Jalaja Potluri, Jacqueline S Garcia.
      Navitoclax (oral B-cell lymphoma-2 family protein inhibitor induces apoptosis of malignant cells in myelofibrosis (MF). We present pooled cohort 1 results from the phase 2 REFINE trial, which evaluated navitoclax plus ruxolitinib (NAV+RUX) for patients with relapsed/refractory MF with suboptimal response to RUX (≥10 mg twice daily stable dose for ≥12 weeks [cohort 1a] or ≥24 weeks [cohort 1b]). Cohort 1a received add-on NAV 50 mg/d, with escalation to ≤300 mg if platelet count was ≥75 × 109/L. Cohort 1b received NAV 100 or 200 mg/d if platelet count was ≤150 or >150 × 109/L, respectively. The primary end point was spleen volume reduction of ≥35% (SVR35) at week 24. Secondary end points included ≥50% total symptoms score (TSS50) reduction at week 24, bone marrow fibrosis (BMF) grade changes, anemia response, and safety. In total, 125 patients received ≥1 dose of NAV+RUX. With median follow-up of 21 months, SVR35 rate was 23% at week 24 and 39% at any time on study (median duration: 11 months). TSS50 rate was 24% at week 24 and 46% at any time on study. BMF improved by ≥1 grade, any time on study, in 39% of patients. Anemia responses were achieved in 23% of patients. Median overall and progression-free survival were 52.3 and 22.1 months, respectively. No new safety signals were observed. The most common adverse event was thrombocytopenia without clinically significant bleeding. NAV+RUX was tolerable and demonstrated early improvement in disease modification parameters in this difficult-to-treat population. This trial was registered at www.ClinicalTrials.gov as #NCT03222609.
    DOI:  https://doi.org/10.1016/j.bneo.2024.100056
  20. Blood Neoplasia. 2025 May;2(2): 100062
    Clinical correlation and prognostic impact of cytogenetic clone size for myelodysplastic syndromes/neoplasm.
    Zhuoer Xie, Najla Al Ali, Ling Zhang, Peter Papenhausen, Virginia Olivia Volpe, Onyee Chan, Andrew Kuykendall, Seongseok Yun, Alison Walker, Kendra Sweet, Jeffrey E Lancet, Eric Padron, David A Sallman, Rami S Komrokji.
      Most myelodysplastic syndromes/neoplasms (MDS) risk stratification models dichotomize conventional cytogenetic abnormalities into present or absent, neglecting the prognostic impact of clone size (percentage of the total cells/metaphases harboring the chromosome abnormality). We investigated the prognostic value of clone size in 1001 patients with MDS using G-banding and fluorescence in situ hybridization. Clone size correlated with anemia severity and thrombocytosis in del(5q) cases, and with anemia and blast percentage in complex karyotypes. TP53 mutation prevalence was significantly elevated in patients with clone size of ≥25% compared with those with <25% (34.2% vs 3%; P = .07). Complex karyotypes with clone size of ≥75% demonstrated superior response to hypomethylating agents (20.8% vs 10%; P = .03). Crucially, clone size of ≥25% independently predicted overall survival and leukemia-free survival, regardless of revised International Prognostic Scoring System (IPSS) or molecular IPSS. Our findings establish clone size as a robust prognostic factor in MDS, warranting its integration into clinical practice and potential incorporation into risk stratification models.
    DOI:  https://doi.org/10.1016/j.bneo.2024.100062
  21. bioRxiv. 2025 May 24. pii: 2025.05.22.655396. [Epub ahead of print]
    Therapy resistance in AML is mediated by cytoplasmic sequestration of the transcriptional repressor IRF2BP2.
    Mark J Althoff, Mohd Minhajuddin, Brett M Stevens, Austin E Gillen, Stephanie Gipson, Sweta B Patel, Ian T Shelton, Regan Miller, Ana Vujovic, Anna Krug, Tracy Young, William M Showers, Monika Dzieciatkowska, Daniel Stephenson, Anit Tyagi, Jana M Ellegast, Tristen Wright, Kimberly Stegmaier, Joseph T Opferman, Angelo D'Alessandro, Clayton A Smith, Craig T Jordan.
      While the development of venetoclax with azacitidine (ven/aza) has improved AML therapy, drug resistance remains a major challenge. Notably, primary ven/aza-resistant AML are frequently reliant on MCL1, however, the underlying mechanisms remain unclear. Co-immunoprecipitation of MCL1 from ven/aza-resistant AML samples coupled with mass spectrometry analysis identified the transcriptional repressor Interferon Regulatory Factor 2 Binding Protein 2 (IRF2BP2) as an MCL1 binding partner. This interaction results in cytoplasmic IRF2BP2 localization and loss of transcriptional repression within ven/aza-resistant leukemic stem cells (LSC). Consequently, ven/aza-resistant LSC have increased IRF2BP2 target gene expression, including acyl-CoA synthetase long-chain family member 1 ( ACSL1 ), an essential rate-limiting enzyme for fatty acid oxidation (FAO). Inhibition of ACSL1 functionally impaired ven/aza-resistant LSC through a depletion of long-chain acyl-carnitine metabolites and FAO. Collectively, these data provide evidence for a previously undescribed mechanism by which MCL1 mediates IRF2BP2 cytoplasmic sequestration and consequent de-repression of ACSL1 , thereby promoting ven/aza-resistance in AML.
    DOI:  https://doi.org/10.1101/2025.05.22.655396
  22. Genes Dis. 2025 Jul;12(4): 101452
    Targeting METTL3 protein by proteolysis-targeting chimeras: A novel therapeutic approach for acute myeloid leukemia.
    Rukiye Nar, Zhixing Wu, Yafang Li, Alexis Smith, Yutao Zhang, Jue Wang, Fang Yu, Sanhui Gao, Chunjie Yu, Zhiguang Huo, Guangrong Zheng, Zhijian Qian.
      Despite numerous studies suggesting that RNA m6A transferase core complex including METTL3 and METTL14 play essential roles in both the initiation and maintenance of acute myeloid leukemia (AML), effective pharmacological targeting of these two proteins remains elusive. Here, we report the development and evaluation of a novel METTL3 degrader, ZW27941, designed to induce METTL3 degradation via the VHL-mediated proteasomal degradation pathway. ZW27941 exhibited potent and selective degradation of METTL3 and its binding partner METTL14, leading to significant anti-leukemic activity in AML cell lines. Furthermore, ZW27941 demonstrated synergistic or additive effects when combined with standard AML therapeutics, such as cytarabine and venetoclax. Our findings suggest that selective METTL3 degraders, exemplified by ZW27941, hold promise as a novel therapeutic approach for AML, particularly when used in combination with existing treatments to enhance efficacy and overcome resistance mechanisms.
    Keywords:  Acute myeloid leukemia; METTL3; PROTAC; Protein degradation; ZW27941
    DOI:  https://doi.org/10.1016/j.gendis.2024.101452
  23. Blood Neoplasia. 2025 May;2(2): 100071
    A phase 2 study of decitabine with or without carboplatin and arsenic trioxide in patients with MDS and AML.
    Patricia L Kropf, Woonbok Chung, Raji Shameem, Lianchun Xiao, Curt Balch, Xuelin Huang, Jean-Pierre J Issa.
      Although decitabine (DAC) shows activity against myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), patient responses are limited, and prognoses remain poor. Preclinical studies have indicated that arsenic trioxide (ATO) and carboplatin (Carbo) enhance DAC's epigenetic gene derepression. Consequently, we initiated a randomized phase 2 clinical trial evaluating DAC alone, or with Carbo or ATO, in patients with MDS/AML. Thirty patients were initially randomized to receive DAC alone (20 mg/m2, days 1-5), DAC plus Carbo (AUC 5, day 8), or DAC plus ATO (0.15 mg/kg, days 1-5), followed by adaptive randomization of 61 patients, based on response rates, for at least three 28-day cycles. The primary endpoint was composite response rate; secondary endpoints included 1-year median survival, safety, and epigenetic effects. Among 91 patients (44 relapsed/refractory), no significant grade 3 or 4 toxicities were observed. Response rates were 26.7% for DAC alone, 14.3% for DAC/Carbo, and 32.3% for DAC/ATO, with DAC/ATO achieving significantly higher responses (P = .041) and more stable disease (P = .018). MDS diagnosis and prior treatment status were key response predictors. Patients with MDS receiving DAC/ATO had the longest survival (16.5 months), compared to DAC/Carbo (4.6 months) and DAC alone (9.3 months) (P = .039). Epigenetic effects were similar across groups. DAC/ATO was well tolerated and improved clinical responses and survival, compared to DAC or DAC/Carbo, particularly in MDS or chronic myelomonocytic leukemia patients. This trial was registered at www.clinicaltrials.gov as #NCT02190695.
    DOI:  https://doi.org/10.1016/j.bneo.2025.100071
  24. bioRxiv. 2025 May 21. pii: 2025.05.16.654547. [Epub ahead of print]
    The Splicing Factor PTBP1 interacts with RUNX1 and is Required for Leukemia Cell Survival.
    Arjun Dhir, Alexander Ethell, Riley Watkins, Calvin Lam, Kevin Tur-Rodriguez, Jimmie Persinger, Kasidy K Dobish, Sipra Panda, Shannon M Buckley, Samantha A Swenson, Sandipan Brahma, M Jordan Rowley, R Katherine Hyde.
      Runt-related Transcription Factor 1 (RUNX1) is essential for definitive hematopoiesis and is among the most frequently mutated genes in leukemia. Previous work from our lab demonstrated that Histone Deacetylase 1 (HDAC1), a known RUNX1 partner, is unexpectedly required for active transcription suggesting a non-histone role for HDAC1 regulating components of the RUNX1 complex. Here, we use proteomics, genomics, and long-read transcriptomics to identify novel RUNX1 interacting partners and decipher their role in gene regulation and RNA splicing in leukemia cells. We demonstrate that Polypyrimidine Tract Binding Protein 1 (PTBP1) interacts with RUNX1 in an HDAC1 dependent manner. Chromatin profiling revealed extensive genome-wide overlap in sites occupied by RUNX1 and PTBP1, with significant enrichment at promoters of actively transcribed genes. Loss of PTBP1 in AML cells led to widespread alterations in RNA splicing and decreased expression of genes whose promoters are bound by both factors, including metabolic genes. In agreement with these findings, we found that loss of PTBP1 reduced glycolysis and glucose uptake and ultimately caused cell death. Based on our data, we propose that the interaction between RUNX1 and PTBP1 facilitates expression of metabolic proteins essential for leukemia cell growth and survival.
    KEY POINTS: PTBP1 binds RUNX1 in a HDAC1-dependent manner and co-localizes to the promoters of target genes in leukemia cells.Loss of PTBP1 decreases expression of key metabolic genes, resulting in decreased cell growth and glycolysis, increased sensitivity to chemotherapy, and cell death.
    DOI:  https://doi.org/10.1101/2025.05.16.654547
  25. Haematologica. 2025 Jun 05.
    Comprehensive characterization of human bone marrow microenvironment shows age-related changes.
    Mareike Peters, Patric Teodorescu, Sergiu Pasca, Xuan Zhang, Rulin Wang, Srinivasan Yegnasubramanian, Leighton H Grimes, Nathan Salomonis, Lukasz P Gondek, Gabriel Ghiaur.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2025.287536
  26. Res Sq. 2025 May 13. pii: rs.3.rs-6528748. [Epub ahead of print]
    Identifying Targeted Therapies for CBFA2T3::GLIS2 Acute Myeloid Leukemia.
    Fanny Gonzales, Constanze Schneider, Gabriela Alexe, Shan Lin, Delan Khalid, Montserrat Alvarez, Allen Basanthakumar, Jana Ellegast, Lucy Merickel, Silvi Salhotra, Audrey Taillon, Mark Wunderlich, Marc Ansari, Jennifer Perry, Barbara Degar, Yana Pikman, Kimberly Stegmaier.
      CBFA2T3::GLIS2 fusion positive pediatric acute myeloid leukemia (AML) remains one of the worst prognostic AML subgroups. To uncover innovative targeted therapeutic approaches in this disease subtype we performed genome-scale CRISPR-Cas9 screening that highlighted a strong, selective dependency on JAK2 compared to other types of cancer. Using a doxycycline-inducible JAK2 knockout (KO) system, we validated JAK2 dependency in CBFA2T3::GLIS2 cell lines, observing impaired proliferation in vitro and in vivo and induced apoptosis with JAK2 KO. Both type I (ruxolitinib) and type II (CHZ868) JAK2 inhibitors showed selective in vitro activity in CBFA2T3::GLIS2 positive AML models. To identify resistance and sensitizer mechanisms to JAK2 inhibitors, we used CRISPR-Cas9 ruxolitinib anchor screening in CBFA2T3::GLIS2 AML. sgRNAs targeting negative regulators of the MAPK pathway were enriched in the ruxolitinib-treated cells. Similarly, CBFA2T3::GLIS2 AML sublines grown to resistance under chronic ruxolitinib treatment expressed pathogenic NRAS mutations. Both approaches converged on MAPK pathway activation as a resistance mechanism to ruxolitinib treatment. Combining ruxolitinib with MEK inhibitors showed a synergistic effect in cell lines and patient-derived xenograft (PDX) cells expressing the fusion and in vivo activity in a CBFA2T3::GLIS2 AML PDX, suggesting a potential approach to target this signaling circuitry in this poor outcome AML subtype.
    DOI:  https://doi.org/10.21203/rs.3.rs-6528748/v1
  27. J Biol Chem. 2025 May 30. pii: S0021-9258(25)02170-2. [Epub ahead of print] 110320
    The transcription factor HOXA9 induces expression of the chromatin modifier SMYD3 to drive leukemogenesis.
    Liping Zhang, Jinqiu Zhong, Luo Yang, Qianyun Ye, Yanli Jin, Chang Liu, Peilong Lai, Hongle Li, Jingxuan Pan, Bei Jin.
      Fusion oncogene MLL-AF9 initiates AML via downstream targets such as HOXA9. Drivers in the complicated settings of advanced AML, however, remain to be incompletely elucidated. Any factors to incur upregulation of the effector HOXA9 predictably aggravate the effect of DOT1L-mediated H3K79 methylation on HOXA9 expression in MLL-AF9-driven AML. In the present study, we identified that SET and MYND domain-containing protein 3 (SMYD3) was overexpressed in AML and predicted a poor prognosis for AML patients. Given that H3K4me3 typically activates the transcription of oncogenes, we hypothesized that SMYD3-catalyzed H3K4me3 may directly increase HOXA9 transcription, offering an additional regulation layer to HOXA9 gene transcription activation in MLL-AF9 AML. We tested this hypothesis and unveiled that SMYD3 is responsible for mediating H3K4me3 enrichment and for independently activating HOXA9 transcription. Transcription factor HOXA9 in turn bound to the promoter region of SMYD3 and enhanced its transcription. The resultant vicious circle of SMYD3-H3K4me3-HOXA9 exacerbated proliferation and blocked differentiation in both AML cell lines and primary cells fractionated from patients with AML. Combinational disruption of this loop and DOT1L inhibition led to enhanced anti-leukemia activity against MLL-AF9 AML in vitro and in vivo. In conclusion, our findings may advocate the current understanding regarding the underlying mechanism and offer SMYD3 as a promising intervention target to override the complicated settings in advanced AML.
    Keywords:  AML; HOXA9; MLL-AF9; SMYD3; differentiation; positive feedback loop; transcription activation
    DOI:  https://doi.org/10.1016/j.jbc.2025.110320
  28. Cell Rep Med. 2025 May 30. pii: S2666-3791(25)00230-7. [Epub ahead of print] 102157
    Senescence and inflammation are unintended adverse consequences of CRISPR-Cas9/AAV6-mediated gene editing in hematopoietic stem cells.
    Anastasia Conti, Kety Giannetti, Federico Midena, Stefano Beretta, Nicolò Gualandi, Rosaria De Marco, Edoardo Carsana, Angelica Varesi, Teresa Tavella, Laura Alessandrini, Parinaz Zarghamian, Alessandra Weber, Samuele Ferrari, Chiara Brombin, Diego Gilioli, Lucrezia Della Volpe, Stephanie Z Xie, Ivan Merelli, Toni Cathomen, Luigi Naldini, Raffaella Di Micco.
      Gene editing (GE) using homology-directed repair (HDR) in hematopoietic stem and progenitor cells (HSPCs) offers promise for long-range gene correction of inherited genetic disorders. However, cellular responses induced by CRISPR-Cas9/AAV6 engineering impair the long-term repopulating potential of HDR-edited HSPCs, adversely impacting the safety and efficacy of clinical translation. Our study uncovers a durable senescence-like response in genetically engineered HSPCs triggered by p53 and interleukin (IL)-1/nuclear factor κB (NF-κB) activation, which restricts graft size and clonal diversity in long-term transplantation assays. We show that transient p53 inhibition or blocking inflammatory pathways mitigates senescence-associated responses, improving the repopulating capacity of edited HSPCs. Importantly, we identify treatment with Anakinra, an IL-1 signaling antagonist, as a promising strategy to enhance polyclonal output in HDR-edited cells while minimizing genotoxicity risks associated with the editing procedure. Overall, our findings present strategies to overcome key hurdles in HDR-based HSPC gene therapies, providing a framework for enhancing their efficacy and safety in clinical applications.
    Keywords:  CRISPR-Cas9; DNA damage; gene editing; gene therapy; genome integrity; hematopoietic stem cells; inflammatory programs; p53; senescence; viral vectors
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102157
  29. Leuk Res. 2025 May 27. pii: S0145-2126(25)00079-7. [Epub ahead of print]154 107719
    Treatment strategies and survival after ruxolitinib discontinuation in myelofibrosis patients: The Italian RUX-MF multicenter study.
    Francesca Palandri, Massimo Breccia, Erika Morsia, Elena M Elli, Giulia Benevolo, Mario Tiribelli, Eloise Beggiato, Mirko Farina, Giovanni Caocci, Novella Pugliese, Alessia Tieghi, Monica Crugnola, Gianni Binotto, Francesco Cavazzini, Alessandro Isidori, Alessandra Dedola, Emilia Scalzulli, Alessia Moioli, Fabrizio Cavalca, Santino Caserta, Andrea Duminuco, Bruno Martino, Roberto M Lemoli, Daniela Cilloni, Monica Bocchia, Fabrizio Pane, Florian H Heidel, Massimiliano Bonifacio, Giuseppe A Palumbo, Filippo Branzanti, Alessandra Iurlo, Elisabetta Abruzzese.
      
    Keywords:  Myelofibrosis; Propensity score matching; Ruxolitinib; Second-line therapy
    DOI:  https://doi.org/10.1016/j.leukres.2025.107719
  30. Leuk Lymphoma. 2025 Jun 02. 1-12
    Prognostic impact of WBC kinetics after induction therapy in patients with acute myeloid leukemia (AML).
    Jesamine Jany, Jan-Henrik Mikesch, Klaus Wethmar, David Baden, Irina Osiaevi, Georg Lenz, Christoph Schliemann, Alexander Pohlmann.
      Acute myeloid leukemia (AML) is associated with broadly varying white blood cell (WBC) counts at the time of diagnosis and treatment. This study examined the association of WBC kinetics and outcome in 443 patients of '7 + 3' intensively treated AML patients, differentiating between leukocytosis and non-leukocytosis. WBC kinetics like WBC nadir, area under the curve (AUC) and negative slope were assessed by regression analyses adjusted for known risk factors. Leukocytosis was associated with inferior overall survival (OS: HR 0.73; 95% CI 0.569-0.938; p = 0.013), event-free survival (EFS: HR 0.777; 95% CI 0.625-0.966); p = 0.013) and increased early death (ED: p < 0.001) compared to the non-leukocytosis cohort. In patients with leukocytosis - regression analyses identified higher WBC nadir and higher AUC as predictors of worse outcome (WBC: HR 1.176; 95% CI 1.03-1.342; p = 0.017 and AUC: HR 1.001; 95% CI 1-1.003; p = 0.039). In contrary, non-leukocytosis patients presented an even shorter OS the lower their WBC nadir (HR 0.298; 95% CI 0.118-0.751; p = 0.01) and AUC dropped during induction (HR 0.981; 95% CI 0.962-0.999; p = 0.041). Multivariate analyses largely confirmed these effects.
    Keywords:  WBC kinetics; White blood cell count nadir; acute myeloid leukemia; area under the curve; leukocytosis; non-leukocytosis
    DOI:  https://doi.org/10.1080/10428194.2025.2512029
  31. Blood Neoplasia. 2025 May;2(2): 100083
    Multiplex gene editing models of del(7q) reveal combined CUX1 and EZH2 loss drives clonal expansion and drug resistance.
    Matthew R M Jotte, Angela Stoddart, Tanner C Martinez, Raven Moten, Yuqing Xue, Molly K Imgruet, Hunter Blaylock, Henna S Nam, Bonnie Hu, Jermaine Austin, Ningfei An, Saira Khan, Sandeep K Gurbuxani, Megan E McNerney.
      Loss of all or part of chromosome 7 [-7/del(7q)] is recurrent in myeloid neoplasms and associated with a poor response to chemotherapy. Chromosome 7-encoded genes driving drug resistance and the consequences of combinatorial 7q tumor suppressor gene loss have remained unclear, the latter question largely because of the challenges of modeling aneuploidy. Here, we use in silico data mining to uncover 7q genes involved in chemotherapy resistance. We establish murine models of del(7q) clonal hematopoiesis and drug resistance with multiplex CRISPR-Cas9 (CRISPR-associated protein 9)-mediated inactivation of 4 genes, Cux1, Ezh2, Kmt2c, and Kmt2e. Postgenotoxic exposure, combined deficiency of Cux1 and Ezh2 preferentially promotes clonal myeloid expansion in vivo, with compounding defects in DNA damage recognition and repair. Human acute myeloid leukemia cell lines similarly illustrate central roles for CUX1 and EZH2 loss in survival and DNA damage resolution after chemotherapy exposure. Transcriptome analysis reveals combined Cux1 and Ezh2 loss recapitulates gene signatures of -7 patients and defective DNA damage response pathways, to a greater extent than single gene loss. This work reveals a genetic interaction between CUX1 and EZH2, and sheds light on how -7/del(7q) contributes to leukemogenesis and drug resistance characteristic of these adverse-risk neoplasms. These data support the concept of 7q as a contiguous gene syndrome region, in which combined loss of multiple gene drives pathogenesis. Furthermore, our CRISPR-based approach may serve as a framework for interrogating other recurrent aneuploid events in cancer.
    DOI:  https://doi.org/10.1016/j.bneo.2025.100083
  32. bioRxiv. 2025 May 19. pii: 2022.07.22.501030. [Epub ahead of print]
    In vivo CRISPR screening identifies SAGA complex members as key regulators of hematopoiesis.
    Michael S Haney, Archana Shankar, Leonid Olender, Ian Hsu, Masashi Miyauchi, Róbert Pálovics, Grace A Meaker, Satoshi Kaito, Ola Rizq, Hwei Minn Khoo, Yavor Bozhilov, Kyomi J Igarashi, Joydeep Bhadury, Christy Munson, Paul K Mack, Tze-Kai Tan, Jan Rehwinkel, Atushi Iwama, Tony Wyss-Coray, Hiromitsu Nakauchi, Adam C Wilkinson.
      The biological mechanisms that sustain the vast blood production required for healthy life remain incompletely understood. To search for novel regulators of hematopoiesis, we performed genome-wide in vivo hematopoietic stem cell (HSC)-based CRISPR knockout screens for regulators of hematopoiesis. We discovered SAGA complex members, including Tada2b and Taf5l , as key regulators of hematopoiesis. Loss of Tada2b or Taf5l strongly inhibited hematopoiesis in vivo , led to a buildup of immature hematopoietic cells in the bone marrow, and was associated with upregulation of interferon pathway genes. Loss of these factors also enhanced the cell outgrowth and the interferon pathway in an in vivo human myelodysplastic syndrome model, suggesting that loss of SAGA complex activity could contribute to hematological disease progression. In summary, this study has identified the SAGA complex as an important regulator of hematopoiesis.
    DOI:  https://doi.org/10.1101/2022.07.22.501030
  33. Transplant Cell Ther. 2025 Jun 02. pii: S2666-6367(25)01207-2. [Epub ahead of print]
    Pilot Study of Low-Dose Splenic Irradiation and Transplantation in JAK Inhibitor-Refractory Myelofibrosis with Splenomegaly.
    Kristin Rathje, Nico Gagelmann, Artur Schneider, Johanna Richter, Christina Rautenberg, Catherina Lueck, Christine Wolschke, Hans Christian Reinhardt, Francis Ayuk, Thomas Schroeder, Nicolaus Kröger.
       BACKGROUND: Splenomegaly is a hallmark feature of myelofibrosis, driven by extramedullary hematopoiesis due to progressive bone marrow fibrosis. Enlarged spleens cause significant symptoms, impair quality of life, and complicate hematopoietic stem cell transplantation (HSCT) by increasing the risk of delayed engraftment, graft failure, and relapse. While Janus kinase (JAK) inhibitors can reduce spleen size, some patients remain refractory or lose response over time. Splenic irradiation has emerged as an alternative strategy, though optimal protocols and safety profiles remain unclear.
    OBJECTIVE: In this bicentric observational study, we evaluated the safety and efficacy of a standardized low-dose splenic irradiation protocol administered immediately prior to HSCT in patients with myelofibrosis and refractory splenomegaly.
    STUDY DESIGN: We included 11 patients with primary or secondary myelofibrosis who underwent first HSCT from 2020 to 2025. Patients received standardized low-dose splenic irradiation of 3.0 Gy fractionated into three or six daily sessions using volumetric modulated arc therapy (VMAT), administered either shortly before or partially concurrently with the conditioning regimen. We systematically monitored spleen size, hematologic parameters, molecular clearance of driver mutations, donor chimerism, and transplant-related outcomes.
    RESULTS: Median spleen size before irradiation was 25 cm, which significantly decreased to 22 cm post-irradiation (median reduction: 3 cm) and further reduced to 17.7 cm by engraftment (median additional reduction: 4.3 cm). All patients achieved neutrophil engraftment within a median of 12 days and platelet engraftment was achieved by 82% within 14 days. Isolated hyperbilirubinemia occurred transiently in 82% of patients without significant clinical consequences. No occurrences of veno-occlusive disease, thrombotic microangiopathy, or hemorrhagic complications were reported. At days 30 and 100 post-transplant, full donor chimerism was achieved in 91% and 80%, with driver mutation clearance observed in 70% and 80%, respectively. With a median follow-up of 5.5 months, overall survival was 91%, with two cases of early relapse and two instances of acute graft-versus-host disease. Two patients experienced poor graft function, one requiring stem cell boost.
    CONCLUSIONS: Our study demonstrates that low-dose splenic irradiation prior to HSCT is an effective and safe adjunct treatment for managing splenomegaly in myelofibrosis patients. The standardized protocol resulted in substantial spleen size reduction, favorable engraftment kinetics, and acceptable toxicity profiles. These promising outcomes highlight splenic irradiation as a viable, less invasive alternative to splenectomy, warranting further exploration in larger prospective trials to refine protocols and confirm long-term benefits.
    Keywords:  allogeneic hematopoietic cell transplant; myelofibrosis; splenic irradiation
    DOI:  https://doi.org/10.1016/j.jtct.2025.05.023
  34. Blood Neoplasia. 2024 Jun;1(2): 100010
    A novel application of XPO1 inhibition for the treatment of myelofibrosis.
    Megan Metzger, Zachary M Avigan, Pankit Vachhani, Julian Waksal, John Mascarenhas.
      Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by constitutional symptoms, progressive cytopenias, and splenomegaly. Activating mutations in the JAK/STAT pathway and cytokine dysregulation driving bone marrow fibrosis and extramedullary hematopoiesis underlie the pathobiology of MF. Although multiple JAK inhibitors are currently approved and provide significant symptom improvement, these agents do not possess disease course modifying potential. Additionally, outcomes are poor for patients who fail JAK inhibitors, highlighting the need for novel mechanism-based therapies and innovative combination strategies. Selinexor, a novel Exportin 1 (XPO1) inhibitor that blocks nuclear export, increases nuclear localization and activity of p53 and other tumor suppressor pathways and decreases cytoplasmic activation of multiple proliferative and profibrotic pathways. Selinexor currently has approved indications in multiple myeloma and lymphoma, with broad potential applications in other malignancies, although it can be limited by toxicity in some settings. Selinexor has shown clinical activity and tolerability in MF, both as monotherapy and, particularly, in combination with ruxolitinib. The collective, early phase trial data support a phase 3 randomized, registration study of selinexor and ruxolitinib in patients with MF naïve to JAK inhibitor therapy. Further work is needed to elucidate the role of XPO1 inhibition as a potential disease-modifying strategy to improve outcomes in MF.
    DOI:  https://doi.org/10.1016/j.bneo.2024.100010
  35. bioRxiv. 2025 May 17. pii: 2025.05.14.653587. [Epub ahead of print]
    Targeted Irradiation and STAT3 Inhibition Reprogram the AML Microenvironment and Extend Survival: Toward Translational Immunoradiotherapy.
    Srideshikan Sargur Madabushi, Jamison Brooks, Darren Zuro, Yu-Lin Su, Damian Kaniowski, Hemendra Ghimire, Ji Eun Lim, Amr Mohamed Hamed Abdelhamid, Ya-Huei Kuo, Guido Marcucci, Jeffrey Wong, Monzr Al Malki, Anthony Stein, Marcin Kortylewski, Susanta Hui.
       Purpose: Despite advances in acute myeloid leukemia (AML) therapy, relapses remain challenging. While AML is radiation-sensitive, total body irradiation (TBI) causes organ toxicities and activates tolerogenic/proangiogenic STAT3 signaling. CSI-2, a myeloid cell-targeted STAT3 inhibitor, promotes anti-leukemic immune responses but has limited efficacy against high disease burden. We investigated whether image-guided targeted marrow irradiation (TMI), which focuses radiation on leukemia sites while sparing critical organs, could synergize with CSI-2 to improve leukemia clearance and establish durable immunity.
    Methods: Mice were intravenously engrafted with CMM-AML cells reaching 20-30% in bone marrow (BM) infiltration (moderate-to-high disease burden) before receiving IV-injections of CSI-2 (5mg/kg) with or without TMI. Fluorescently labeled CSI-2 biodistribution was assessed using flow cytometry and quantitative multiphoton microscopy. Survival was monitored for 3-4 months before evaluating BM composition using flow cytometry and immunohistochemistry.
    Results: TMI significantly improved vascular permeability and scavenger receptor/TLR9-dependent uptake of CSI-2 by AML cells and leukemia-associated myeloid cells. Combined TMI/CSI-2 treatment more effectively reduced high leukemia burden than CSI-2 alone, achieving >80% survival at 120 days with increased CD8+ cytotoxic and CD4+ helper T cell infiltration. TMI/CSI-2-treated mice were protected from AML rechallenge suggesting that they developed protective immune memory. In an aggressive MLL-AF9 AML model, TMI/CSI-2 combination significantly extended survival compared to either monotherapy.
    Conclusion: TMI/CSI-2 strategy represents a novel organ-sparing immunoradiotherapy that synergistically enhances leukemia clearance while promoting long-term protective immunity. These findings warrant further investigation of this strategy for high-burden or relapsed AML and provide the foundation for clinical translation.
    DOI:  https://doi.org/10.1101/2025.05.14.653587
  36. Sci Adv. 2025 Jun 06. 11(23): eads6556
    CoREST in pieces: Dismantling the CoREST complex for cancer therapy and beyond.
    Houssam Ismail, Jalila Chagraoui, Guy Sauvageau.
      Several landmark studies over the past decade have uncovered a critical role of the CRL3KBTBD4 ubiquitin ligase complex in regulating stability of corepressor of repressor element 1 silencing transcription factor (CoREST) complex proteins and normal hematopoietic stem cell self-renewal. There is now mounting evidence that the CoREST complex plays oncogenic roles, although the contributions of its catalytic versus noncatalytic functions remain unclear. Here, we summarize and discuss mechanisms whereby the CoREST complex coopts tissue-specific transcription factors to elicit pathogenic activity in cancer and neurodegenerative disease. We also identify tumor types with selective dependencies on the scaffolding properties of the CoREST complex. We argue that these tumor types may benefit from a KBTBD4-activating/CoREST complex degrader therapy, which could also enhance antitumor immunity and sensitize resistant tumors to immunotherapy. Overall, understanding how the CoREST complex operates abnormally and differences between its targeting through catalytic inhibitors or protein degraders will help discern all possible applications for targeting therapies now in clinical development.
    DOI:  https://doi.org/10.1126/sciadv.ads6556
  37. Blood Neoplasia. 2025 May;2(2): 100073
    Clonal composition of karyotypically normal AML at diagnosis is not affected by the microenvironment.
    Monika M Toma, Adam Karami, Margaret Nieborowska-Skorska, Tomasz Skorski.
      
    DOI:  https://doi.org/10.1016/j.bneo.2025.100073
  38. Blood Adv. 2025 Jun 05. pii: bloodadvances.2025016212. [Epub ahead of print]
    Impact of Concomitant Azoles on Ruxolitinib Treatment in Patients With GVHD: Post Hoc Analyses of REACH2 and REACH3.
    Zahra Mahmoudjafari, Emily Kintsch, Zhenyi Xue, Valkal Bhatt, John Galvin, Franco Locatelli, Robert Zeiser.
      Azole antifungal agents, commonly used for preventing invasive fungal infections in graft-versus-host disease (GVHD), are known to affect ruxolitinib metabolism. Post hoc analyses of the REACH2/REACH3 phase 3 trials (ClinicalTrials.gov: NCT02913261/NCT03112603) examined the impact of these clinically relevant drug interactions on ruxolitinib treatment outcomes in patients with steroid-refractory acute GVHD (aGVHD; REACH2) and steroid-refractory/steroid-dependent chronic GVHD (cGVHD; REACH3). In REACH2, the overall response rate (ORR) at Day 28 was significantly higher with ruxolitinib versus best available therapy (BAT; 67.5% vs 44.3%; P=0.0003) among patients who received concomitant azoles; among those who did not, Day 28 ORR was 45.9% vs 28.6%, respectively. In REACH3, ORR at Week 24 was significantly higher with ruxolitinib versus BAT in patients who did (46.6% vs 29.4%; P=0.006) or did not receive (57.1% vs 19.4%; P<0.0001) concomitant azoles. Concomitant azoles neither increased the rate of cytopenias in patients treated with ruxolitinib in REACH2/REACH3, nor impacted the median (range) dose of ruxolitinib up to Day 28 in REACH2 (azoles/no azoles, 20.0 [9.0-21.0]/20.0 [8.4-20.0] mg/day) or Week 24 in REACH3 (azoles/no azoles, 19.4 [4.8-20.5]/19.9 [5.5-20.0] mg/day). However, patients receiving concomitant azoles were more likely to have ruxolitinib dose modifications in REACH2/REACH3, highlighting the importance of dose optimization in these patients. Overall, concomitant azole treatment was generally well tolerated and did not affect treatment outcomes with appropriate ruxolitinib dose optimization. Consistent with primary REACH2/REACH3 results, ruxolitinib provided greater clinical benefit than BAT in patients with steroid-refractory aGVHD and steroid-refractory/steroid-dependent cGVHD, irrespective of concomitant azole treatment.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016212
  39. Blood Neoplasia. 2024 Jun;1(2): 100011
    Competition of dual SF3B1 mt clones in MDS-RS is associated with distinct RNA mis-splicing in hematopoietic stem cells.
    Pedro Luis Moura, Yasuhito Nannya, Affaf Aliouat, Isabel Juliana Hofman, Teresa Mortera-Blanco, Tetsuichi Yoshizato, Ryunosuke Saiki, Masahiro M Nakagawa, Maria Creignou, Ann-Charlotte Björklund, Gunilla Walldin, Indira Barbosa, Monika Jansson, Francesca Grasso, Edda M Elvarsdottir, Petter S Woll, Sten Eirik W Jacobsen, Seishi Ogawa, Eva Hellström-Lindberg.
      
    DOI:  https://doi.org/10.1016/j.bneo.2024.100011
  40. Blood Adv. 2025 Jun 05. pii: bloodadvances.2024015286. [Epub ahead of print]
    Adult thymectomy is associated with increased mortality risk from cancer but not cardiovascular disease.
    Kameron Allen Kooshesh, Brody Harry Foy, Richard A Baylis, Karin Gustafsson, Daniel A Zlotoff, Tomas G Neilan, David T Scadden.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2024015286
  41. Blood Neoplasia. 2025 May;2(2): 100069
    A feedforward loop between ACLY and MYC supports T-ALL progression in vivo.
    Victoria da Silva-Diz, Amartya Singh, Maya Aleksandrova, Oekyung Kim, Christopher Thai, Olga Lancho, Patricia Renck Nunes, Hayley Affronti, Alexia Martínez de Paz, Steven Z Josefowicz, Xiaoyang Su, Kathryn E Wellen, Daniel Herranz.
      T-cell acute lymphoblastic leukemia (T-ALL) is a hematological malignancy in need of novel therapeutic approaches. Here, we identify ATP-citrate lyase (ACLY) as overexpressed in human T-ALL and as a promising therapeutic target for its treatment. To test the effects of ACLY in leukemia progression, we developed an isogenic model of NOTCH1-induced Acly conditional knockout leukemia. Importantly, we observed intrinsic antileukemic effects upon loss of ACLY, which further synergized with NOTCH1 inhibition in vivo. Metabolomic profiling upon ACLY loss revealed a metabolic crisis with reduced acetyl-coenzyme A (acetyl-CoA) levels and decreased oxygen consumption rate. Gene expression profiling analyses showed that the transcriptional signature of ACLY loss very significantly correlates with the signature of MYC loss in vivo. Mechanistically, the decrease in acetyl-CoA led to reduced H3K27ac levels in Myc, resulting in transcriptional downregulation of Myc and drastically reduced MYC protein levels. Moreover, pharmacological inhibition of ACLY led to reduced MYC levels and antileukemic effects in human T-ALL cell lines and patient-derived xenografts. Interestingly, our analyses also revealed a reciprocal relationship whereby ACLY itself is a direct transcriptional target of MYC, thus establishing a feedforward loop that is important for leukemia progression. Overall, our results identified a relevant ACLY-MYC axis and unveiled ACLY as a novel promising target for T-ALL treatment.
    DOI:  https://doi.org/10.1016/j.bneo.2025.100069
  42. bioRxiv. 2025 May 24. pii: 2025.05.20.655224. [Epub ahead of print]
    Cheminformatic identification of small molecules targeting acute myeloid leukemia.
    Megan R Daneman, Bernadetta Meika, Elissa Tjahjono, Alexey V Revtovich, Leonid A Stolbov, Scott R Gilbertson, Vladimir V Poroikov, Natalia V Kirienko.
      Acute myeloid leukemia (AML) is an aggressive hematological malignancy that has poor prognosis and high relapse rates with cytotoxic chemotherapeutics. Previously, we identified modulators of mitochondrial function, PS127-family compounds, that were cytotoxic to AML and were characterized by two predicted functions: apoptotic agonism and thioredoxin/glutathione reductase inhibition (T/GRi). Here, we uncovered a third critical predicted function: autophagic induction. A cheminformatics screening of ∼4.2 million compounds for molecules with high probability of these three functions yielded 93 hits, 81 of which were closely related to PS127-family molecules. In silico hits selected for validation selectively killed AML cells, activated apoptosis, required functional autophagy, and interfered with glutathione metabolism, confirming predicted functions. This increased pools of cytosolic and mitochondrial ROS and decreased oxygen consumption and ATP synthesis. Differential scanning fluorimetry implicated glutathione reductase as a direct target of these molecules. Structurally-unrelated compounds from different clusters caused the same phenotype, validating our structure-blind screening approach. Furthermore, strong synergy between these compounds and the AML treatment midostaurin underscores their therapeutic potential.
    DOI:  https://doi.org/10.1101/2025.05.20.655224
  43. Blood Neoplasia. 2024 Sep;1(3): 100021
    Instructive interaction between myelodysplastic hematopoiesis and the bone marrow microenvironment at the single-cell level.
    Johann-Christoph Jann, Nanni Schmitt, Alexander Streuer, Qingyu Xu, Vladimir Riabov, Eva Altrock, Nadine Weimer, Verena Nowak, Julia Obländer, Iris Palme, Melda Göl, Marie Demmerle, Felicitas Rapp, Fabian Siegel, Laurenz Steiner, Mahmoud Ghazal, Angelika Duda, Verena Haselmann, Ali Darwich, Ahmed Jawhar, Mohamad Jawhar, Georgia Metzgeroth, Wolf-Karsten Hofmann, Daniel Nowak.
      Myelodysplastic neoplasms (MDS) are hypothesized to remodel their bone marrow (BM) microenvironment to reinforce conditions for their propagation. In this study, we investigated interactions between MDS cells and the BM niche at single-cell level. In a patient-derived xenograft (PDX) model, we analyzed 13 000 cells from different murine niche cell populations after long-term (>24 weeks) exposure to MDS vs healthy human grafts. Subsequently, we analyzed over 24 000 primary human BM cells enriched for the nonhematopoietic compartment by using whole bone fragments from n = 8 patients with MDS and n = 7 healthy, age-matched donors. In PDX who received MDS transplantation, mesenchymal cell (MSC) subpopulations were forced to overexpress hematopoietic factors such as Cxcl12 and Il7 upon contact with hematopoietic MDS cells as compared with healthy grafts. Single-cell analyses of primary in situ BM cells from patients with MDS showed highly heterogeneous MSC subpopulations on a patient-individual level. We identified inflammatory gene expression profiles as well as overexpression of C-X-C Motif Chemokine Ligand 12, KIT ligand, and Interleukin 7 in MDS MSCs and endothelial cells. In conclusion, we demonstrate reprogramming of the BM microenvironment by MDS cells, pointing to altered MSC subpopulations with increased growth factor expression profiles in a subgroup of patients with MDS.
    DOI:  https://doi.org/10.1016/j.bneo.2024.100021
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