bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2026–08–16
24 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Evaluating response criteria in myelodysplastic/myeloproliferative neoplasms: a systematic review and meta-analysis.
  2. MDS without clonal marker: when depth outperforms breadth.
  3. Bridging TP53-mutated myelodysplastic syndrome/acute myeloid leukemia to transplant: is venetoclax part of the answer?
  4. Survival outcomes and treatment patterns in myelofibrosis in the JAK inhibitor era.
  5. Real-world patterns of treatment intensity and prognostic model performance in older acute myeloid leukemia: insights from the French ALFA-PPP Cohort.
  6. RNA terminal uridylyl transferases are druggable vulnerabilities in AML but are dispensable for normal hematopoiesis.
  7. Allogeneic hematopoietic cell transplantation for myelodysplastic syndromes harboring a paroxysmal nocturnal hemoglobinuria clone-a study on behalf of the Chronic Malignancies and Severe Aplastic Anemia Working Parties of the EBMT.
  8. Maintenance therapy after allogeneic stem cell transplantation for relapse prevention in myeloid malignancies.
  9. Clinical outcomes associated with NPM1 mutations in newly diagnosed acute myeloid leukemia.
  10. TIM3-targeted delivery of venetoclax overcomes drug resistance and reinvigorates NK cell activity in acute myeloid leukemia.
  11. Tunable universal OR-gated CAR T cells for AML.
  12. Prognostic value of measuring LSC frequency in AML: a systematic review and meta-analysis.
  13. The FOLR2-IRF2BP2 axis mediates erythropoiesis impairment by excess folic acid in myelodysplastic neoplasms.
  14. EZH2 Inhibition and Myeloid Risk: A Feature of On-Target Biology.
  15. Multilayer modeling reveals an endogenous retrovirus signature predictive of induction chemotherapy failure in AML.
  16. Do FLT3 and KIR3DL1 converge on a common immune surveillance axis in treatment-free remission of chronic myeloid leukemia?
  17. Venetoclax plus azacitidine, low-dose cytarabine, aclarubicin, and G-CSF (VA-CAG regimen) for newly diagnosed young patients with acute myeloid leukemia: A prospective, multicenter, single-arm Phase II clinical trial.
  18. Boosting anti-leukemia cytotoxicity of CD4 and CD8 T cells through combined inhibition of MEK and HDAC.
  19. Targeting oncogenic FLT3 uncovers a ferroptosis vulnerability through selenocysteine recoding in acute myeloid leukaemia.
  20. FERMT3 alternative splicing enhances kindlin-3 membrane recruitment for neutrophil adhesion during stress myelopoiesis.
  21. Mutant p53 reactivation and DNA demethylation in the treatment of AML/MDS.
  22. Beyond BCL-2: What drives venetoclax resistance in acute myeloid leukemia?
  23. Total body irradiation is associated with increased burden of cerebral microbleeds in haematopoietic stem cell transplant recipients.
  24. Janus kinase inhibitors after ruxolitinib failure in myelofibrosis: A systematic review and pooled analysis of phase 3 efficacy and integrated safety across clinical trials and real-world evidence.
  1. Blood Neoplasia. 2026 Aug;3(3): 100266
    Evaluating response criteria in myelodysplastic/myeloproliferative neoplasms: a systematic review and meta-analysis.
    Anthony M Hunter, Somedeb Ball, Rena Buckstein, Catherine Cargo, Melissa Fischer, Devendra Hiwase, Raphael Itzykson, Sanam Loghavi, Luca Malcovati, Moshe Mittelman, Eric Padron, Mrinal M Patnaik, Valeria Santini, Daniel Thomas, Arjan A Van de Loosdrecht, Daniel H Wiseman, Blanca Xicoy, Michael R Savona, Douglas Tremblay.
      
    DOI:  https://doi.org/10.1016/j.bneo.2026.100266
  2. Leukemia. 2026 Aug 10.
    MDS without clonal marker: when depth outperforms breadth.
    Sandra Huber, Marietta Truger, Stephan Hutter, Heiko Mueller, Veronika Ecker, Gregor Hoermann, Torsten Haferlach, Manja Meggendorfer.
      
    DOI:  https://doi.org/10.1038/s41375-026-03096-w
  3. Curr Opin Hematol. 2026 Aug 13.
    Bridging TP53-mutated myelodysplastic syndrome/acute myeloid leukemia to transplant: is venetoclax part of the answer?
    Peter Zhao, Samuel Urrutia.
       PURPOSE OF REVIEW: TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) remain among the most challenging myeloid malignancies, with poor long-term outcomes despite allogeneic stem cell transplantation (HCT). Venetoclax-based regimens produce encouraging response rates, but their role as optimal pre-transplant therapy for TP53 mutated MDS/AML remains unconfirmed. This review evaluates the rationale and clinical evidence supporting venetoclax as a bridging strategy to HCT.
    RECENT FINDINGS: Recent studies have refined risk stratification through TP53 allelic-state characterization, demonstrating poor transplant outcomes. Studies show venetoclax-based therapy may induce deeper and faster remissions. A higher proportion of patients who receive venetoclax successfully transition to transplantation. However, higher response rates do not consistently translate into a survival advantage post-transplant. Efforts to study venetoclax regimens in the pre-transplant setting lack stratification by TP53 allelic state or design focus for this subgroup.
    SUMMARY: Current evidence supports venetoclax as an acceptable bridging strategy to accelerate response and cytoreduction for TP53-mutated MDS/AML. There is a limited number of studies of venetoclax-containing regimens specific for transplant eligible patients with TP53 mutated MDS/AML. It is important for future studies to incorporate a standardized TP53 allelic-state assessment, molecular measurable residual disease evaluation, and transplant-specific endpoints.
    Keywords:  TP53; acute myeloid leukemia; allogeneic hematopoietic cell transplantation; myelodysplastic syndrome; venetoclax
    DOI:  https://doi.org/10.1097/MOH.0000000000000949
  4. Br J Haematol. 2026 Aug 04.
    Survival outcomes and treatment patterns in myelofibrosis in the JAK inhibitor era.
    Spanish MPN Group (GEMFIN)
      Data on real-world survival and treatment patterns in large, unselected myelofibrosis (MF) cohorts remain limited. We analysed 1649 patients with MF diagnosed from 2010 onwards and included in the Spanish Myelofibrosis Registry across 64 centres. Janus kinase (JAK) inhibitors were administered to approximately half of the patients. Among those aged ≤70 years with intermediate-2/high-risk International Prognostic Scoring System (IPSS), only 25% ultimately underwent transplantation. Median survival was 6.6 years, with no significant differences between primary and secondary MF; acute leukaemia was the most frequent cause of death, accounting for 20% of cases. Compared with a matched general population, relative survival at 5 and 10 years was 68% and 44% respectively. The reduction in relative survival was more pronounced in patients aged >65 years and in male patients, two subgroups that also exhibited a higher burden of comorbidities and a greater frequency of high molecular risk mutations. Remarkably, patients in the high-risk IPSS category had a 10-year relative survival of only 12%; however, survival reduction was not confined to high-risk disease, with divergence from expected survival emerging early among lower-risk categories. These findings highlight the persistent impact of MF on life expectancy in the contemporary JAK inhibitor era and the need for improvement in its overall management.
    Keywords:  IPSS; JAK inhibitor; myelofibrosis; ruxolitinib; survival; transplantation; treatment
    DOI:  https://doi.org/10.1111/bjh.70723
  5. Leukemia. 2026 Aug 11.
    Real-world patterns of treatment intensity and prognostic model performance in older acute myeloid leukemia: insights from the French ALFA-PPP Cohort.
    Lin Pierre Zhao, Céline Berthon, Laurene Fenwarth, Stephane De Botton, Thomas Cluzeau, Laure Farnault, Sylvain Chantepie, Pierre Arnautou, Thorsten Braun, Mathieu Leclerc, Delphine Lebon, Ahmad Aljijakli, Isabelle Plantier, Ollivier Legrand, Juliette Lambert, Christophe Willekens, Emmanuel Raffoux, Claire Bories, Emilie Lemasle, Kevin-James Wattebled, Ambroise Marcais, Celia Salanoubat, Pascal Turlure, Jamile Frayfer, Benjamin Carpentier, Madalina Uzunov, Reda Garidi, Iona Vaida, Renaud Buffet, Alexandra Coelho, Karine Celli-Lebras, Raphael Itzykson, Claude Preudhomme, Nicolas Duployez, Hervé Dombret, Lionel Adès.
      
    DOI:  https://doi.org/10.1038/s41375-026-03110-1
  6. Sci Adv. 2026 Aug 14. 12(33): eaec3399
    RNA terminal uridylyl transferases are druggable vulnerabilities in AML but are dispensable for normal hematopoiesis.
    Christopher Mapperley, Elise Georges, Ali A Azar, Yuka Kabayama, Hannah Lawson, Iwo Kucinski, Derek George, Joana Campos, Corey Fyfe, Jozef Durko, Wei Y Chan, Lewis Allen, Babak Jazayeri, Edward Blacker, Louie N van de Lagemaat, Aurelien Tripp, Theodoros I Roumeliotis, Giulia Guiducci, Eleanor Herbert, Jasmin Paris, Jyoti Choudhary, George Poulogiannis, Robert M Campbell, Marcos Morgan, Lovorka Stojic, Folkert J Van Werven, Douglas Vernimmen, Berthold Göttgens, Dónal O'Carroll, Kamil R Kranc.
      Acute myeloid leukemia (AML) is an aggressive hematological malignancy arising from hematopoietic stem and progenitor cells (HSPCs). Current treatments often fail to eradicate AML; therefore, new therapeutic strategies are essential. Here, we reveal that RNA terminal uridylyl transferase enzymes 4 and 7 (TUT4/7) are druggable therapeutic targets, whose genetic deletion suppresses AML growth, induces apoptosis, and improves the survival in leukemic mouse models. Notably, a preclinical TUT4/7 inhibitor promotes cell death in samples from patients with AML and synergizes with venetoclax. Mechanistically, TUT4/7 inactivation suppresses mevalonate pathway gene expression, compromising the cholesterol synthesis pathway. Current AML therapies often cause severe hematopoietic toxicity. Although Tut4/7 deletion results in inflammatory activation throughout the hematopoietic system, this is permissive to a normal life span and Tut4/7 deficiency does not compromise HSPC function. Together, these findings identify TUT4/7 as druggable targets, whose inactivation suppresses AML while sparing normal hematopoiesis. In combination with venetoclax, this represents a promising therapeutic strategy.
    DOI:  https://doi.org/10.1126/sciadv.aec3399
  7. Bone Marrow Transplant. 2026 Aug 13.
    Allogeneic hematopoietic cell transplantation for myelodysplastic syndromes harboring a paroxysmal nocturnal hemoglobinuria clone-a study on behalf of the Chronic Malignancies and Severe Aplastic Anemia Working Parties of the EBMT.
    Joanna Drozd-Sokolowska, Patrick Gilbert, Joe Tuffnell, Linda Koster, Grzegorz Helbig, Uwe Platzbecker, Pavel Jindra, Carlo Borghero, Thomas Cluzeau, Matthias Eder, Francis Ayuk, Francesco Onida, Carmelo Gurnari, Christof Scheid, Kavita Raj, Régis Peffault de Latour, Antonio Risitano, Marie Robin, Donal P McLornan.
      
    DOI:  https://doi.org/10.1038/s41409-026-03007-8
  8. Curr Opin Hematol. 2026 Aug 13.
    Maintenance therapy after allogeneic stem cell transplantation for relapse prevention in myeloid malignancies.
    Nihar Desai, Ivan Pasic.
       PURPOSE OF REVIEW: Relapse remains the leading cause of treatment failure after allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), and outcomes after relapse are poor. This review summarizes and critically appraises current evidence for post-HCT maintenance therapy aimed at relapse prevention.
    RECENT FINDINGS: Patient selection increasingly rests on disease risk and the presence of a targetable mutation. FLT3 inhibitors carry the strongest evidence: randomized trials support sorafenib and gilteritinib in FLT3 internal tandem duplication (FLT3-ITD) AML, and the MORPHO trial showed that measurable residual disease (MRD) status identifies patients most likely to benefit. Isocitrate dehydrogenase (IDH) inhibitors and menin inhibitors are promising but lack randomized data. For patients without actionable mutations, hypomethylating agent maintenance has produced inconsistent results, and the evidence more strongly supports MRD-triggered preemptive therapy.
    SUMMARY: Post-HCT maintenance has shifted from broadly applied, poorly tolerated regimens toward targeted, MRD-guided strategies. Important uncertainties remain regarding optimal patient selection, agent choice, timing, and duration. Adequately powered, HCT-specific randomized trials with standardized MRD endpoints are the principal unmet need.
    Keywords:  acute myeloid leukemia; allogeneic hematopoietic cell transplantation; fLT3 inhibitors; maintenance therapy; myelodysplastic syndrome
    DOI:  https://doi.org/10.1097/MOH.0000000000000948
  9. Cancer. 2026 Aug 15. 132(16): e70568
    Clinical outcomes associated with NPM1 mutations in newly diagnosed acute myeloid leukemia.
    Aziz Farhat, Georgina El Hajjar, Hagop Kantarjian, Koji Sasaki, Nicholas J Short, Branko Cuglievan, Sanam Loghavi, Keyur Patel, Alex Bataller, Wei Ying Jen, Musa Yilmaz, Guillermo Montalban-Bravo, Danielle Hammond, Naveen Pemmaraju, Naval Daver, Farhad Ravandi, Elias Jabbour, Tapan Kadia, Gautam Borthakur, Guillermo Garcia-Manero, Courtney D DiNardo, Ghayas C Issa.
       BACKGROUND: Nucleophosmin 1-mutated (NPM1mt) acute myeloid leukemia (AML) is associated with a relatively favorable prognosis though long-term outcomes remain suboptimal without clear predictors identified by therapy.
    METHODS: In a retrospective analysis, the authors identified 396 patients (18%) with newly diagnosed (ND) NPM1mt AML treated at The University of Texas MD Anderson Cancer Center and analyzed their outcomes. Using a Cox regression model, they analyzed predictors of survival in newly diagnosed NPM1mt AML across various therapies.
    RESULTS: Those treated with high intensity chemotherapy had a median overall survival (OS) of 84.7 months with a 5-year rate of 53% (95% CI, 44%-61%) whereas those treated with a combination of a hypomethylating agent (HMA) and venetoclax had a median OS of 23.3 months with a 5-year rate of 19% (95% CI, 5%-39%). The combination of cladribine, low-dose cytarabine, and venetoclax alternating with azacitidine and venetoclax yielded better survival compared with HMA and venetoclax in an age-matched analysis (5-year OS rate of 74% vs. 24%) (p = .048).
    CONCLUSION: Among patients with NPM1mt treated with high-intensity chemotherapy, older age, a poor performance status, and presence of a FLT3-ITD mutation or extramedullary disease predicted a worse overall survival. For patients treated with a hypomethylating agent and venetoclax, older age was the only predictor of worse long-term outcomes. These findings can be used for risk-stratification of newly diagnosed NPM1mt AML and provide benchmarks of response and survival for this subtype.
    Keywords:  acute; azacitidine; cladribine; cytarabine; leukemia; mutation; myeloid; nucleophosmin; prognosis; retrospective studies; venetoclax
    DOI:  https://doi.org/10.1002/cncr.70568
  10. Nat Cancer. 2026 Aug 12.
    TIM3-targeted delivery of venetoclax overcomes drug resistance and reinvigorates NK cell activity in acute myeloid leukemia.
    Qiwei Wang, Jingyi Li, Xin Zeng, Lina Liu, Huan Lu, Yin Zhao, Yan Huang, Rui Wang, Chen Wang, Yingli Han, Yishan Ye, Yanmin Zhao, Jimin Shi, Yi Luo, Weiyan Zheng, Yongxian Hu, Shibing Wang, Xiangmin Tong, He Huang, Shanshan Pei, Pengxu Qian.
      Acute myeloid leukemia (AML) remains challenging, especially for older or unfit individuals who develop resistance to venetoclax (VEN)-based regimens. Although TIM3 represents a promising AML target, clinical blockade has yielded suboptimal outcomes. Here, we develop VINCENT (VEN-integrated natural killer cell engager targeting TIM3), a therapeutic platform combining anti-CD16 and anti-TIM3 antibodies with nanoformulated VEN. In VEN-resistant AML cell lines and patient-derived xenograft models, VINCENT overcomes resistance by enhancing VEN delivery, eliminating TIM3+ blasts and dysfunctional T cells and activating natural killer (NK) cells. In primary AML samples, VINCENT selectively kills drug-resistant blasts, with efficacy correlating with the NK cell-to-TIM3+ blast ratio. Single-cell transcriptomics reveals VINCENT depletes high-TIM3 blasts and remodels the immunosuppressive microenvironment toward immune competence. Collectively, VINCENT simultaneously addresses VEN resistance, NK cell dysfunction and immune evasion, offering a personalized option for elderly or unfit individuals with AML failing standard VEN regimens.
    DOI:  https://doi.org/10.1038/s43018-026-01217-z
  11. iScience. 2026 Aug 21. 29(8): 117008
    Tunable universal OR-gated CAR T cells for AML.
    Menna Y Siddiqui, Jingyao Chen, Joey Zhuoying Huang, Madeline Loffredo, Seunghee Lee, Han Deng, Yongshuai Li, Nelia Leemans, Tim Lu, Brian S Garrison, Marcela Guzmán Ayala, Nicholas W Frankel, Wilson W Wong.
      Acute myeloid leukemia (AML) is characterized by antigen heterogeneity and poor prognosis. Here, to tackle the heterogeneity of AML, we combined FLT3 with CD33 in a combinatorial OR-gate approach using our split, universal, programmable (SUPRA) chimeric antigen receptor (CAR) platform. The split platform affords tunability over activation levels and multiplexed targeting. We characterized the specificity and sensitivity of different SUPRA CAR adapters for each target across a panel of target cell lines. Our results demonstrate that this CAR system can effectively target two antigens with equivalent efficacy to conventional CARs while reducing the engineering burden of designing CAR T cells against multiple antigens. Furthermore, we can characterize an effective dose range where off-target cytotoxicity against hematopoietic stem and progenitor cells is minimized. Our SUPRA OR gate has the potential to provide an effective and safer solution to treating AML.
    Keywords:  AML; CAR; OR gate; universal
    DOI:  https://doi.org/10.1016/j.isci.2026.117008
  12. Blood Adv. 2026 Aug 14. pii: bloodadvances.2026021094. [Epub ahead of print]
    Prognostic value of measuring LSC frequency in AML: a systematic review and meta-analysis.
    Tom Reuvekamp, Marry Lin, Lok Lam Ngai, Kasper J Croese, Kirsten A Ziesemer, Mitra Nekouei Shahraki, Vera M R von Pickartz, Lukas H Haaksma, Arjan A van de Loosdrecht, Sylvie D Freeman, David C de Leeuw, Jacqueline Cloos.
      Leukemia stem cells (LSC) are thought to be responsible for relapse in patient with acute myeloid leukemia (AML). LSC can be quantified at diagnosis to improve risk stratification, and during follow-up to monitor residual disease. To systematically evaluate the prognostic relevance of measuring LSC at diagnosis and in remission in patients with AML, we conducted a systematic and reconstructed individual patient data meta-analysis. We performed a comprehensive search for studies that reported overall survival (OS) and/or event-free survival (EFS) in relation to LSC measurements at diagnosis or in remission. We reconstructed individual patient data based on Kaplan Meier curves. Fifty-six studies were included, including a total of 44 cohorts (n=7781) for OS and 37 cohorts (n=5032) for EFS at diagnosis, and 19 cohorts (n=2006) for OS and 22 cohorts (n=1342) for EFS in remission. Positive LSC status was significantly associated with inferior OS and EFS at diagnosis (OS: hazard ratio [HR] 1.96 (1.85-2.08); EFS: HR 2.32 (2.15-2.49)) and in remission (OS: HR 2.59 (2.23-3.03); EFS: HR 2.53 (2.18-2.94)). To conclude, we found that measuring LSC has prognostic relevance both at diagnosis and in remission. This supports LSC frequency as a key prognostic factor that warrants implementation into clinical practice.
    DOI:  https://doi.org/10.1182/bloodadvances.2026021094
  13. Leukemia. 2026 Aug 10.
    The FOLR2-IRF2BP2 axis mediates erythropoiesis impairment by excess folic acid in myelodysplastic neoplasms.
    Chaoying Yang, Yanpeng Wang, Yuanliang Peng, Zeyuan Wang, Zhiming Guo, Xiaojuan Xiao, Haobo Li, Han Gong, Bin Hu, Li Liu, Min Fu, Pengfei Cao, Xiongbing Yang, Jing Liu, Ling Nie, Xu Han, Ji Zhang.
      Myelodysplastic neoplasms (MDS) are a group of heterogeneous clonal hematopoietic disorders with a high risk of progression to acute myeloid leukemia. Despite folic acid being an essential vitamin for human development that can be harmful at high levels, it is still unclear how its excess precisely impacts erythropoiesis in MDS patients. Based on non-targeted metabolomics, we identified significantly elevated folic acid levels in both MDS mice and MDS patients. Functional studies revealed that an excess folic acid diet exacerbated anemia in MDS mice, while restricted folic acid intake alleviated disease phenotypes. Mechanistically, excess folic acid promotes the nuclear translocation of FOLR2, which functions as a transcription factor to bind the promoter of IRF2BP2 and drive its expression. Upregulated IRF2BP2 subsequently represses key erythroid transcription factors GATA1 and KLF1, leading to erythroid differentiation arrest. The folic acid-FOLR2-IRF2BP2 axis is upregulated, and high IRF2BP2 expression correlates with poor prognosis in MDS patients. Our study unveils a novel pathological role of folic acid in promoting MDS progression by disrupting hematopoietic stem/progenitor cells and impairing erythropoiesis, suggesting dietary folic acid restriction and targeting FOLR2-IRF2BP2 axis as potential therapeutic strategies. The FOLR2-IRF2BP2 Axis Mediates Erythropoiesis Impairment by Excess Folic Acid in Myelodysplastic Syndromes. In NUP98-HOXD13 transgenic/MDS mice, folic acid content was significantly increased. Excess folic acid diet exacerbated disease symptoms in MDS mice. Reducing folic acid intake significantly alleviated MDS symptoms. Mechanistically, excess folic acid not only promoted the expansion of hematopoietic stem progenitor cells but also disrupted erythropoiesis involving the FOLR2-IRF2BP2 pathway.
    DOI:  https://doi.org/10.1038/s41375-026-03038-6
  14. Clin Cancer Res. 2026 Aug 14.
    EZH2 Inhibition and Myeloid Risk: A Feature of On-Target Biology.
    Joshi J Alumkal, Leigh Ellis.
      In March 2026, Ipsen voluntarily withdrew the EZH2 inhibitor tazemetostat (Tazverik) from all markets and indications following results from the confirmatory Phase Ib/III SYMPHONY-1 trial demonstrating hematologic second primary malignancies (SPMs) in 5.7% of treated patients, compared with none in the control arm. The most frequently reported SPMs were myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Although this finding may be interpreted as an idiosyncratic liability of a single agent, the biology of EZH2 suggests a broader, target-driven risk. EZH2 functions in a context-dependent manner as both an oncogene and a tumor suppressor. Gain-of-function mutations drive transformation in germinal center B-cell lymphomas, whereas loss-of-function alterations impair hematopoietic stem cell differentiation and are recurrent in myeloid malignancies, including MDS and AML. In selected solid tumor contexts, such as specific subtypes of medulloblastoma, EZH2 loss can likewise promote tumorigenesis. These observations raise concern that chronic pharmacologic inhibition of EZH2 may phenocopy loss-of-function states that initiate myeloid neoplasia. We argue that the withdrawal of tazemetostat exposes a fundamental vulnerability in the development of epigenetic therapies: target validation has focused on tumor-intrinsic effects while underweighting consequences in normal stem cell compartments. This issue is particularly relevant for ongoing Phase III programs in prostate cancer, where prolonged exposure may amplify latency-dependent risks. We propose changes to preclinical safety assessment, trial design, and pharmacovigilance to mitigate predictable, target-mediated toxicities.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-26-2216
  15. Blood Neoplasia. 2026 Aug;3(3): 100263
    Multilayer modeling reveals an endogenous retrovirus signature predictive of induction chemotherapy failure in AML.
    Nogayhan Seymen, Sila Gerlevik, I Richard Thompson, Merilyn M Albuquerque, Anastasia Conti, Chi Wai Eric So, Mohammad M Karimi.
      
    DOI:  https://doi.org/10.1016/j.bneo.2026.100263
  16. Leukemia. 2026 Aug 12.
    Do FLT3 and KIR3DL1 converge on a common immune surveillance axis in treatment-free remission of chronic myeloid leukemia?
    Mai Fujita, Hiroshi Ureshino.
      
    DOI:  https://doi.org/10.1038/s41375-026-03113-y
  17. Hemasphere. 2026 Aug;10(8): e70449
    Venetoclax plus azacitidine, low-dose cytarabine, aclarubicin, and G-CSF (VA-CAG regimen) for newly diagnosed young patients with acute myeloid leukemia: A prospective, multicenter, single-arm Phase II clinical trial.
    Xiaoping Li, Qiurong Zhang, Xiaoyan Li, Lin Liu, Yonglin Shen, Yu Li, Lihui Peng, Chaoyang Zhou, Chie Qiu, Zhongtao Yuan, Shiqian Hou, Youcheng Wang, Lihua Zhang, Jingqiong Li, Liang Zhao, Qiuyuan Tang, Zucong Chen, Jing Feng, Xuejuan Zhang, Guoxiu Bao, Kui Zhang, Renpeng Zhang, Shiqi Li, Yingnian Chen, Jianhua Rao, Yancheng Dong, Dingsong Zhang, Yueyuan Wang, Aifang Li, Xi Ye, Lei Lei, Jiao Chen, Sufen Xu, Yanling Jin, Chaoen Zheng, Yang Liang, Sanbin Wang.
      We conducted a prospective, multicenter, Phase II study to evaluate the safety and efficacy of venetoclax/azacitidine/low-dose cytarabine/aclarubicin/granulocyte colony-stimulating factor (G-CSF) (VA-CAG) in young patients with newly diagnosed acute myeloid leukemia (ND-AML). The VA-CAG regimen included venetoclax (100 mg/day, Days 1-2; 200 mg, Day 3; 400 mg/day, Days 4-21), azacitidine (75 mg/m2, Days 1-7), cytarabine (10 mg/m2/12 h, Days 1-7), aclarubicin (12 mg/m2, Days 1, 3, 5, and 7), and G-CSF (5 μg/kg/day, Days 0-8). The primary endpoint was the complete remission (CR) rate after Cycle 1; the secondary endpoints included measurable residual disease (MRD)-negative remission rate, adverse events, and duration of remission (DOR). A total of 120 subjects were enrolled. The median age was 50 years (interquartile range, IQR, 36-57). The CR and composite complete response (CRc) rates were 91% (95% CI 86%-96%) and 95% (95% CI 91%-99%), respectively; 84% (95% CI 81%-88%) of the CRc patients achieved MRD-negative remission. Common Grade ≥4 adverse events included neutropenia (96%), thrombocytopenia (86%), febrile neutropenia (24%), pneumonia (4%), and sepsis (4%). The median times to recovery of absolute neutrophil count (ANC) ≥ 0.5 × 109/L and platelet count ≥ 20 × 109/L for responding patients were 14 days (IQR, 9-19) and 10 days (IQR, 4-16), and the 60-day mortality rate was 0%. With a median follow-up of 22.1 months (95% CI 20.4-23.7 months), 34 subjects subsequently received hematopoietic stem cell transplantation (HSCT). The median DOR values of all patients and the patients who did not receive HSCT were not reached. Hence, the VA-CAG regimen is a safe and effective first-line induction chemotherapy for ND-AML patients.
    DOI:  https://doi.org/10.1002/hem3.70449
  18. Blood. 2026 Aug 04. pii: blood.2026033417. [Epub ahead of print]
    Boosting anti-leukemia cytotoxicity of CD4 and CD8 T cells through combined inhibition of MEK and HDAC.
    Meher Bolisetti Gayatri, Bei Jia, Anthony J Veltri, Vysakh Anandan, Maoshuo Yang, Jing Li, Kenneth Man Hei Chan, Sophie Verbeke, Jiangchen Yao, Sarah E Granozio, Yun Jiang, Esra'a Keewan, Jacqueline Ann Cook, Xiaolan Zhu, Erik A Ranheim, Zhe Wang, Chih-Hsing Chou, Kalyan V Nadiminti, H Leighton Grimes, Marulasiddappa Suresh, Hong Zheng, Xiaona You, Jing Zhang.
      Acute myeloid leukemia (AML) is an aggressive blood cancer with a 5-year overall survival rate of ~30%. Although immunotherapies engaging T cells demonstrate remarkable success in treating many solid tumors and blood cancers, they show little to no efficacy in treating AML. Therefore, immunotherapies are traditionally underappreciated and underdeveloped in AML. Through a drug re-purpose screen, we identified and validated that combined MEK and HDAC inhibitions via trametinib and quisinostat (TQ) potently inhibited the growth of mouse and human NRAS;ASXL1-AML (NA-AML), MLLr, and NPM1 mutated AML cells in vitro. In NA-AML mice, TQ drastically slowed down AML progression and prolonged their survival. The survival benefits of TQ largely relied on T cell functions. We show that TQ synergized to downregulate immune checkpoint ligands and upregulate STAT1- and CIITA-mediated expression of MHC-I and MHC-II in NA-AML cells. In addition, TQ treatment significantly reprogrammed transcriptome and epigenetic landscape of T cells, activated STAT1 signaling, and upregulated genes and pathways promoting activation, survival, and cytotoxicity of CD4 and CD8 T cells. A cytotoxic cluster was thus expanded in central memory and effector memory T cells in TQ-treated NA-AML mice. More importantly, TQ directly acted on AML-associated mouse and human T cells, reverting them from a dysfunctional state to an active state. In leukemia:T cell co-cultures, TQ-treated T cells demonstrated greatly improved MHC-dependent leukemia killing. Our findings suggest that the dual actions of TQ on NA-AML and T cells enhance leukemia recognition and anti-leukemia killing of endogenous T cells, leading to effective AML clearance.
    DOI:  https://doi.org/10.1182/blood.2026033417
  19. Nat Cell Biol. 2026 Aug;28(8): 1715-1727
    Targeting oncogenic FLT3 uncovers a ferroptosis vulnerability through selenocysteine recoding in acute myeloid leukaemia.
    Minhua Li, Yudan Zhu, Yuki Kageyama, Ken Furudate, Ayumi Kitano, Taotao Tan, Mengdie Feng, Jing Zhou, Tao Wang, Robert J Taylor, Alexandra M Stevens, Md Abul Hassan Samee, Jeffrey A Magee, Koichi Takahashi, Daisuke Nakada.
      Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has emerged as a potential therapeutic strategy for therapy-resistant cancers. Glutathione peroxidase 4 and the selenoprotein biosynthesis pathway essential for its translation are key regulators of ferroptosis but lack effective therapeutic targeting. In a drug screening using a selenoprotein translation reporter, here we identify FMS-like tyrosine kinase 3 (FLT3) inhibitors as suppressors of selenoprotein translation that induce ferroptosis in FLT3-mutant acute myeloid leukaemia. Mechanistically, FLT3 inhibition disrupts selenocysteine recoding, in which a UGA stop codon is recoded as selenocysteine via the SECIS element and associated binding proteins. Notably, the antileukemic efficacy of the FLT3 inhibitor gilteritinib was markedly reduced by dietary vitamin E, which attenuated ferroptosis. This study highlights ferroptosis as a vulnerability in FLT3-mutant acute myeloid leukaemia and suggests that high vitamin E intake may compromise tyrosine kinase inhibitor efficacy partly by suppressing ferroptosis.
    DOI:  https://doi.org/10.1038/s41556-026-02016-5
  20. Blood. 2026 Aug 10. pii: blood.2026034274. [Epub ahead of print]
    FERMT3 alternative splicing enhances kindlin-3 membrane recruitment for neutrophil adhesion during stress myelopoiesis.
    Serena Lee, Gulinare Halimu, Madeleine Sophie Vidal, Xiaojia Song, Neil J Ball, Klaus Ley, Benjamin T Goult, Lai Wen.
      Leukocyte Adhesion Deficiency syndrome type III (LAD-III) is characterized by recurrent infections and is caused by FERMT3 gene mutations. FERMT3 encodes two isoforms, a standard kindlin-3 and a longer splicing variant, which differs by the addition of four residues Ile-Pro-Arg-Arg (IPRR) in the pleckstrin homology (PH) domain (kindlin-3-IPRR). Previous studies suggested that kindlin-3-IPRR was dysfunctional in inducing neutrophil adhesion, attributed to altered phospholipid binding of the IPRR-containing PH domain. Here we show that kindlin-3-IPRR is fully functional in activating β2 integrins and promotes neutrophil adhesion. The IPRR insert enhances phospholipid binding in vitro and promotes association of kindlin-3 with the plasma membrane. By analyzing RNA sequencing datasets of neutropoiesis, we show that the kindlin-3 short isoform lacking IPRR is highly expressed in neutrophil precursors but downregulated in mature neutrophils. In contrast, a higher proportion of the long isoform was detected in hematopoietic stem cells (HSCs) and mature neutrophils. Kindlin-3-IPRR supports robust adhesion of HSCs. We propose that kindlin-3-IPRR may be crucial in conditions requiring rapid neutrophil mobilization. Indeed, kindlin-3 splicing is altered in neutrophils from patients undergoing stress myelopoiesis after exposure to granulocyte colony-stimulating factor (G-CSF) or HSC transplantation (HSC-T) compared with healthy donors. During stress myelopoiesis induced by G-CSF treatment, the kindlin-3 long isoform is selectively upregulated in mature neutrophils, coinciding with enhanced β2 integrin activation. These findings support a model in which alternative splicing of FERMT3 dynamically fine-tunes integrin activation and leukocyte adhesion during hematopoietic stress, with potential implications for monitoring hematopoietic recovery after HSC transplantation.
    DOI:  https://doi.org/10.1182/blood.2026034274
  21. Sci Transl Med. 2026 Aug 12. 18(862): eads9325
    Mutant p53 reactivation and DNA demethylation in the treatment of AML/MDS.
    Huaxin Song, Xinjie Chen, Shujun Xiao, Jiaqi Wu, Yuting Dai, Wen Wu, Yu Wu, Xiangqin Weng, Jiachun Song, Ni Yan, Chenjing Ye, Fangfang Shi, Jingyi Cui, Derun Zheng, Hesong Zhang, Kai Tan, Xueqin Chen, Sujiang Zhang, Jiale Wu, Min Lu.
      Acute myeloid leukemia/myelodysplastic syndromes (AML/MDSs) carrying p53 mutations are refractory to various standard therapies. Arsenic trioxide (ATO) may be effective in restoring function to p53 structural mutants. Here, we report that mutant p53 rescued by ATO treatment strengthened interferon responses triggered by the DNA hypomethylating agent decitabine by transactivating interferon regulatory factor 7 (IRF7) directly. Decitabine also increased the transactivation activity of ATO-rescued mutant p53 by inducing p53-serine-20 phosphorylation and blocking p53-inhibitory mouse double minute 2 homolog (MDM2). ATO and decitabine together killed p53-mutant AML cells and suppressed tumor growth in cell line-derived xenografts. In a first-in-human pilot clinical trial for testing the combination of ATO and decitabine (PANDA-T0 trial, NCT03855371), which enrolled five patients with AML/MDS harboring p53 structural mutations, the ATO and decitabine regimen produced manageable adverse events, and four of the five treated patients achieved complete remission at the level of the bone marrow, associated with p53 activation and interferon response. In 103 p53-mutant patients whose samples were deposited in Ruijin AML/MDS sample repository, 48 distinct p53 missense mutants were identified, 21 of which were classified as ATO and decitabine regimen applicable because of their competencies in activating p53 and interferon responses upon cotreatment. This study establishes an alternative treatment regimen for patients with p53-mutant AML/MDS and provides a proof-of-concept framework for p53-targeted therapy that differentiates between p53 mutations.
    DOI:  https://doi.org/10.1126/scitranslmed.ads9325
  22. Cancer Cell. 2026 Aug 10. pii: S1535-6108(26)00313-2. [Epub ahead of print]44(8): 1525-1532
    Beyond BCL-2: What drives venetoclax resistance in acute myeloid leukemia?
    Anna Skwarska, Marina Konopleva.
      The BCL-2 inhibitor venetoclax has transformed outcomes for older or frail patients with acute myeloid leukemia (AML), and its resistance mechanisms are becoming better defined, including compensatory and lineage-associated switches toward MCL-1 or BCL-xL dependence, oncogenic signaling activation, blast phenotype, and differentiation stage. Additional putative mechanisms-such as emerging BAX mutations, mitochondrial structure remodeling, integrated stress response, and metabolic adaptations, including enhanced amino acid uptake and fatty acid oxidation to sustain oxidative phosphorylation-require further validation.
    DOI:  https://doi.org/10.1016/j.ccell.2026.07.004
  23. Br J Haematol. 2026 Aug 12.
    Total body irradiation is associated with increased burden of cerebral microbleeds in haematopoietic stem cell transplant recipients.
    Jure Hederih, Asad Charania, Camelia Vladescu, Ira Lacej, Richard Szydlo, Jiri Pavlu, Renuka Palanicawandar, Jose Ros-Soto, Andrew Innes, Dragana Milojkovic, Eduardo Olavarria, Jane Apperley, Adam Waldman, Nichola Cooper.
      
    Keywords:  cerebral microbleeds; haematopoietic stem cell transplant; total body irradiation
    DOI:  https://doi.org/10.1111/bjh.70747
  24. Br J Haematol. 2026 Aug 14.
    Janus kinase inhibitors after ruxolitinib failure in myelofibrosis: A systematic review and pooled analysis of phase 3 efficacy and integrated safety across clinical trials and real-world evidence.
    Andrea Duminuco, Patrick Harrington, Elena Torre, Hillary Catellani, Novella Pugliese, Matteo Pacilli, Annalisa Santisi, Arianna Sbriglione, Giuseppe A Palumbo.
      Ruxolitinib remains first-line standard of care for symptomatic myelofibrosis, but resistance/intolerance develops in most patients. Three Janus kinase inhibitors (JAKis) have entered the post-ruxolitinib space via distinct pivotal trials. We systematically searched prospective trials evaluating JAKi in refractory adults with myelofibrosis. Efficacy was assessed across phase 3 trials, with safety integrating phase 2 and real-world data. Pooled ≥35% spleen volume reduction at week 24 was 32.7% (95% confidence intervals 27.3-38.6) for fedratinib, 15.8% (11.7-21.0) for momelotinib and 21.6% (13.8-32.3) for pacritinib 200 mg bis in die; pooled ≥50% Total Symptom Score reduction rates were 32.8% (27.4-38.7), 25.3% (20.2-31.3) and 32.4% (22.9-43.7) respectively. Across safety datasets (n = 1004 trial; n = 790 real-world), fedratinib showed the highest grade ≥3 anaemia (34.3%) and any-grade diarrhoea (56.6%), whereas momelotinib the lowest (8.0%). Pacritinib carried the greatest risk of grade ≥3 bleeding (11.2%). Discontinuation due to adverse events was comparable across agents (~16%-17%). Real-world evidence from five momelotinib cohorts (n = 580) identified nephrotoxicity (glomerular filtration rate decline 17%-29%) and peripheral neuropathy (4%-20%) as monitoring targets. Despite limitations from differing study designs, each post-ruxolitinib JAKi shows a distinct efficacy/safety fingerprint mapping onto a phenotype, guiding second-line choice by clinical factors and prior adverse events.
    Keywords:  fedratinib; momelotinib; myelofibrosis; pacritinib; pooled analysis; ruxolitinib failure; systematic review
    DOI:  https://doi.org/10.1111/bjh.70754
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