bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2026–03–22
seventeen papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. IDH1 and IDH2 mutated myeloid neoplasms: mutational pattern, clonal hierarchy and the role in AML transformation.
  2. Comparative effectiveness of HMA with venetoclax vs intensive chemotherapy in AML with very high-risk cytogenetics.
  3. Discovery and preclinical activity of the menin-KMT2A inhibitor ziftomenib in acute leukemia models.
  4. DNA Methylation Stochasticity is Linked to Transcriptional Variability and Convergent Epigenetic Disruption Across Genetic Subtypes of Acute Myeloid Leukemia.
  5. Polθ activity modulates sensitivity to standard therapies in DNMT3A-deficient leukemia.
  6. Telomere length and clonal hematopoiesis interact to influence outcomes in hematopoietic stem cell transplantation.
  7. Decreased Chronic GvHD With Post-Transplant Cyclophosphamide Versus ATG in Patients With Myelofibrosis Allografted With an Unrelated Donor: A Study From the Chronic Malignancies Working Party of the EBMT.
  8. Protein S-acylation dynamics provide metabolic plasticity to acute myeloid leukemia cells.
  9. A real-world analysis of the impact of azole antifungal prophylaxis on outcomes in patients with newly diagnosed acute myeloid leukemia treated with venetoclax-based therapy.
  10. Targeting BMP and TAZ/TEAD mechanotransduction pathways impairs acute myeloid leukemia chemoresistance.
  11. Preliminary Safety and Efficacy of Navitoclax Plus Ruxolitinib in Janus Kinase Inhibitor-Naïve Patients With Myelofibrosis From the Multicenter, Open-Label, Phase 2 Study (REFINE).
  12. Aberrant Kupffer-like differentiation of hematopoietic stem cell is critical for the MDS pathogenesis in Setd2-deficient mice.
  13. Inhibition of p300/CREBBP catalytic activity drives context-dependent transcriptional activation in AML.
  14. Phase 1b study of ABBV-744, a novel, selective BET inhibitor, as monotherapy in patients with myelofibrosis.
  15. FBXO3-mediated DUSP9 ubiquitination promotes leukemia stem cell maintenance and tyrosine kinase inhibitor resistance in chronic myeloid leukemia.
  16. Randomized trial of GvHD Prophylaxis in Haploidentical PBSC Transplantation: ATG, PTCy, and Low-Dose Combination Therapy.
  17. Chromatin reorganization drives overexpression of a Btaf1 variant underpinning hematopoietic aging.
  1. Blood Adv. 2026 Mar 20. pii: bloodadvances.2025019387. [Epub ahead of print]
    IDH1 and IDH2 mutated myeloid neoplasms: mutational pattern, clonal hierarchy and the role in AML transformation.
    Sandra Huber, Flora Goessweiner, Wencke Walter, Isolde Summerer, Manja Meggendorfer, Rainer Ordemann, Christian Pohlkamp, Niclas Kneisel, Claudia Haferlach, Wolfgang Kern, Torsten Haferlach, Sabit Delic, Gregor Hoermann.
      Mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 are recurrently found in patients with myeloid neoplasms (MN) and clinically targeted by small molecule inhibitors. We aimed to comprehensively study the genetic pattern and underlying clonal architecture in a large cohort of 12 071 patients (acute myeloid leukemia (AML; n=4 113), myelodysplastic neoplasms (MDS; n=6 316), or chronic myelomonocytic leukemia (CMML; n=1 642)). IDH mutations were found in 28% of AML (IDH1: 10%; IDH2: 18%), 6.3% of MDS (IDH1: 1.8%; IDH2: 4.6%), and 5.2% of CMML patients (IDH1: 0.8%; IDH2: 4.4%). IDH mutations were enriched in subgroups with increased blasts but almost absent within MDS-biTP53. The co-mutational pattern differed by age, between the MN, and also between mutation hotspots. The underlying clonal hierarchy suggested that IDH mutations were present in the founder clone in many, but not all cases. Finally, the high frequencies of IDH1 mutations in secondary AML and AML-MR (both 9.5%) compared to MDS (1.8%) and CMML (0.8%) indicated a frequent acquisition of this mutation at the transition to AML which was directly confirmed in a subset of patients analyzed before and after progression. Overall, our findings have potential implications for sequential molecular testing and targeted treatment decisions.
    DOI:  https://doi.org/10.1182/bloodadvances.2025019387
  2. Blood Neoplasia. 2026 May;3(2): 100201
    Comparative effectiveness of HMA with venetoclax vs intensive chemotherapy in AML with very high-risk cytogenetics.
    Luis E Aguirre, Jan Philipp Bewersdorf, Yiwen Liu, Rory M Shallis, Leora Boussi, Andrius Zucenka, Sylvain Garciaz, Rebecca P Bystrom, Daniel J DeAngelo, Richard M Stone, Marlise R Luskin, Jacqueline S Garcia, Eric S Winer, Kelly Ling, Evan C Chen, Martha Wadleigh, Guillaume Berton, Eytan M Stein, Aaron D Goldberg, Lourdes Mendez, Amer M Zeidan, David A Sallman, Shai Shimony, Maximilian Stahl.
      The optimal frontline therapy for acute myeloid leukemia (AML) with very high-risk cytogenetics (vHRC)-defined by complex karyotype (CK), monosomal karyotype (MK), or inv(3)/t(3;3)-remains uncertain. We retrospectively analyzed 358 newly diagnosed AML-vHRC cases treated at five academic centers (2014-2024), stratified by intensive chemotherapy (IC) vs hypomethylating agent plus venetoclax (HMA+ven). Cytogenetic features included CK in 90.2%, MK in 64%, and inv(3)/t(3;3) in 9.8%; TP53 mutations occurred in 51%. Frontline therapy was IC in 40% and HMA+ven in 60%, with a median age of 67 years (range, 22-92). Median overall survival (OS) for AML-vHRC was 8 months compared with 31 months for non-vHRC AML (P < .0001). Composite complete remission (cCR) rates were similar with IC vs HMA+ven (55% vs 54%, P = .91). Patients with inv(3)/t(3;3) had inferior responses (cCR 36%) compared with CK/MK-AML (67%; P < .001). No OS differences by frontline regimen were observed among patients aged 60-75 years (7.7 vs 6.6 months, P = 0.43), those with TP53-mutated disease (8.1 vs 5.8 months, P = .17), or following allogeneic hematopoietic stem cell transplantation (alloHSCT; 35 vs 25 months, P = .56). On multivariable analysis, older age (HR 1.02, P = .0003), inv(3)/t(3;3) (HR 2.12, P = .0002), and TP53mt (HR 2.07, P < .0001) independently predicted inferior OS, whereas alloHSCT improved OS (HR 0.42, P < .0001); frontline regimen (HMA+ven vs IC) was not associated with OS (HR 0.84, P = .2814). In AML-vHRC, IC and HMA+ven yield comparable remission and survival outcomes. Given equivalent efficacy and similar early mortality, HMA+ven represents a reasonable frontline option for patients aged 60-75 years, those with TP53mt disease, and patients intended for alloHSCT.
    DOI:  https://doi.org/10.1016/j.bneo.2026.100201
  3. Blood. 2026 Mar 18. pii: blood.2025031201. [Epub ahead of print]
    Discovery and preclinical activity of the menin-KMT2A inhibitor ziftomenib in acute leukemia models.
    Hongzhi Miao, Tao Wu, Trupta Purohit, Dong Chen, Szymon Klossowski, Dmitry Borkin, Bradley Clegg, Joshua Martin Ray, SeRa Park, Rhiannon Stevens, EunGi Kim, Katarzyna Kempinska, Yi Wang, Miao He, Bo Wen, Joshua W Goldman, Jennifer E Agrusa, Chao Ding, Maria Luisa Sulis, Duxin Sun, Rajen Mody, Annette S Kim, Pingda Ren, Lian-Sheng Li, Yi Liu, Francis Burrows, Linda Kessler, Tomasz Cierpicki, Jolanta Grembecka.
      The protein-protein interaction between menin and KMT2A (histone lysine methyltransferase 2A) plays a critical role in acute leukemia with KMT2A rearrangements, nucleophosmin 1 (NPM1) mutations and nucleoporin 98 rearrangements, and represents an emerging opportunity for therapeutic intervention. Here, we report development and comprehensive evaluation of the activity of ziftomenib as an orally bioavailable, highly potent and selective small molecule inhibitor of the menin-KMT2A interaction. In leukemia cells and primary patient samples with the menin-KMT2A dependency, ziftomenib profoundly inhibited proliferation, reduced clonogenic potential and induced differentiation, which was associated with strong downregulation of the menin-KMT2A target genes, including MEIS1, HOXA9 and HOXB2. In xenografts and patient-derived xenograft models of KMT2A-rearranged leukemia, ziftomenib induced leukemia regression or reduced leukemia burden, accompanied by a pronounced reduction of the menin-KMT2A target genes. We next assessed ziftomenib against four MEN1 (gene encoding menin) mutants (T349M, M327I, G331R, G331D) associated with clinical resistance to another menin inhibitor revumenib. Ziftomenib retained anti-leukemic activity against T349M mutant cells and demonstrated low-nanomolar potency (GI50≤25 nM) against G331R cells, despite several-fold reduced potency relative to MEN1 wild-type cells, whereas M327I and G331D mutants were resistant. The crystal structures of ziftomenib in complex with menin wild-type, T349M or G331R mutants revealed a similar binding mode of ziftomenib to these menin variants, rationalizing potent inhibitory activity towards these mutants. Ziftomenib has recently received FDA approval for adult patients with NPM1-mutated acute myeloid leukemia and continues to be evaluated clinically in leukemias with NPM1 or KMT2A alterations, both as monotherapy and in combinations.
    DOI:  https://doi.org/10.1182/blood.2025031201
  4. Cancer Res. 2026 Mar 16.
    DNA Methylation Stochasticity is Linked to Transcriptional Variability and Convergent Epigenetic Disruption Across Genetic Subtypes of Acute Myeloid Leukemia.
    Eleanor Hilgart, Weiqiang Zhou, Eduardo Martinez-Montes, Rakel Tryggvadottir, Lukasz P Gondek, Ravindra Majeti, Hongkai Ji, Michael A Koldobskiy, Andrew P Feinberg.
      Disruption of the epigenetic landscape is of particular interest in acute myeloid leukemia (AML) due to its relatively low mutational burden and frequent occurrence of mutations in epigenetic regulators. Here, we applied an information-theoretic analysis of methylation potential energy landscapes, capturing changes in mean methylation level and methylation entropy, to comprehensively analyze DNA methylation stochasticity in subtypes of AML defined by mutually exclusive genetic mutations. AML subtypes with CEBPA double mutation and those with IDH mutations were identified as distinctly high-entropy subtypes, marked by methylation disruption over a convergent set of genes. The analysis revealed a core program of epigenetic landscape disruption across all AML subtypes; discordant methylation stochasticity, transcriptional dysregulation, and altered chromatin accessibility converged on functionally important leukemic signatures. Demonstration of a relationship between methylation entropy and gene expression variability connected the disruption of the epigenetic landscape to transcription in AML. Finally, the hypomethylating drug decitabine led to reduction of DNA methylation entropy specifically in IDH2-mutant AML cells. Overall, this approach identified a convergent program of epigenetic dysregulation in leukemia, clarifying the contribution of specific genetic mutations to stochastic disruption of the epigenetic and transcriptional landscapes of AML.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-5822
  5. Cell Rep Med. 2026 Mar 17. pii: S2666-3791(26)00104-7. [Epub ahead of print]7(3): 102687
    Polθ activity modulates sensitivity to standard therapies in DNMT3A-deficient leukemia.
    Bac Viet Le, Umeshkumar Vekariya, Monika M Toma, Margaret Nieborowska-Skorska, Marie-Christine Caron, Malgorzata Gozdecka, Zayd Haydar, Martin Walsh, Jayashri Ghosh, Elaine Vaughan-Williams, Paulina Podszywalow-Bartnicka, Anna-Mariya Kukuyan, Sylwia Ziolkowska, Jessica Atkins, Emir Hadzijusufovic, Gurushankar Chandramouly, Reza Nejati, Katarzyna Piwocka, Richard Pomerantz, George S Vassiliou, Brian J P Huntly, Peter Valent, Mariusz Wasik, Alfonso Bellacosa, Jean-Yves Masson, Gaorav P Gupta, Grant A Challen, Tomasz Skorski.
      Myeloid malignancies carrying somatic DNMT3A mutations (DNMT3Amut) are refractory to standard therapy. DNMT3Amut leukemia cells accumulate toxic DNA double-strand breaks (DSBs) and stalled replication forks, rendering them dependent on DNA damage response (DDR). We report here that DNA polymerase theta (Polθ), a key element in DSB repair by end-joining (Polθ-mediated end-joining [TMEJ]) and in fork restarting, promotes survival and proliferation of DNMT3Amut leukemia cells. Polθ is overexpressed in DNMT3Amut leukemia cells due to abrogation of PARP1 PARylation-dependent UBE2O E3 ligase-mediated ubiquitination and proteasomal degradation of Polθ. In addition, PARP1-mediated recruitment of the SMARCAD1-MSH2/MSH3 repressive complex to DSBs is diminished in DNMT3Amut leukemia cells, which facilitates association of Polθ with DNA damage. Polθ inhibitors enhance the anti-leukemic effects of standard drugs such as FLT3 kinase inhibitor quizartinib, cytarabine ± doxorubicin, and etoposide in vitro and in mice with DNMT3Amut leukemia. Altogether, Polθ is an attractive target in DNMT3Amut hematological malignancies.
    Keywords:  DNA polymerase theta; DNMT3A-deficient acute myeloid leukemia; PARP1; TMEJ; replication fork; ubiquitination
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102687
  6. Blood Adv. 2026 Mar 20. pii: bloodadvances.2025018279. [Epub ahead of print]
    Telomere length and clonal hematopoiesis interact to influence outcomes in hematopoietic stem cell transplantation.
    Jake Tobin, Patrick Stelmach, Sarah Richter, Diane Xu, Sandra Sauer, Marc S Raab, Muxin Gu, William Grant Dunn, Margarete A Fabre, Carsten Müller-Tidow, George S Vassiliou.
      Clonal hematopoiesis (CH), the clonal expansion of a hematopoietic stem cell (HSC) and its progeny driven by somatic mutations, has been associated with inferior survival outcomes amongst recipients of autologous stem cell transplants (ASCT). Leukocyte telomere length (LTL) has a complex but well-documented interaction with CH, but the impact of this interaction on stem cell transplantation (SCT) has not been adequately examined. We measured LTL in graft cell DNA from 452 patients undergoing ASCT for myeloma, for whom targeted DNA sequencing for CH driver gene mutations was available. We interrogated clinical and longitudinal large-scale laboratory data for these patients to understand the impact of graft LTL on progression-free (PFS) and overall survival (OS) post-transplantation, as well as blood count indices and their trajectories. In multivariate analyses, longer LTL was associated with increased PFS amongst patients without CH. However, this protective association was not seen in patients with CH. We also report that amongst patients with CH, longer LTL was associated with an increased red cell distribution width (RDW) prior to myeloablative chemotherapy and after ASCT. Collectively, these data reveal hitherto undescribed interactions between LTL, CH and ASCT outcomes.
    DOI:  https://doi.org/10.1182/bloodadvances.2025018279
  7. Am J Hematol. 2026 Mar 20.
    Decreased Chronic GvHD With Post-Transplant Cyclophosphamide Versus ATG in Patients With Myelofibrosis Allografted With an Unrelated Donor: A Study From the Chronic Malignancies Working Party of the EBMT.
    Yves Chalandon, Edouard F Bonneville, Diderik-Jan Eikema, Liesbeth C de Wreede, Linda Koster, Joe Tuffnell, Jakob Passweg, Johannes Schetelig, Uwe Platzbecker, Ibrahim Yakoub-Agha, Urpu Salmenniemi, Mareike Verbeek, Moniek A de Witte, Jean-Baptiste Méar, John A Snowden, Tobias A W Holderried, Gwendolyn van Gorkom, Frédéric Baron, Marie Robin, Xavier Poiré, Mieke W H Roeven, Maija Itälä-Remes, Jan Zaucha, Kavita Raj, Joanna Drozd-Sokolowska, Giorgia Battipaglia, Tomasz Czerw, Juan Carlos Hernández-Boluda, Nicola Polverelli, Donal P McLornan.
      
    Keywords:  ATG; allogeneic hematopoietic stem cell transplantation; myelofibrosis; post‐transplant cyclophosphamide; unrelated donor
    DOI:  https://doi.org/10.1002/ajh.70288
  8. bioRxiv. 2026 Mar 03. pii: 2026.03.02.708949. [Epub ahead of print]
    Protein S-acylation dynamics provide metabolic plasticity to acute myeloid leukemia cells.
    Nithya Balasundaram, Ayşegül Erdem, Azeem Sharda, Veerle W Daniels, Phillip L Chea, Fleur Leguay, Youzhong Liu, Mark A Keibler, Charles Vidoudez, Andrew A Lane, Didier Vertommen, Hans Casteur, Michaël R Laurent, Sunia A Trauger, Gregory Stephanopoulos, David T Scadden, Nick van Gastel.
      Though cancer cells' altered metabolism has been recognized for a century, the clinical success of metabolic targeting remains limited due to metabolic plasticity. Here, we use acute myeloid leukemia (AML) as a model to investigate this adaptability through combinatorial metabolic compound screening. Synthetic lethality emerged when AML cells were simultaneously treated with a glutaminase inhibitor and TOFA, a hypolipidemic agent. Sensitivity to this combination was also seen in primary patient samples and in other cancer types, while healthy hematopoietic progenitors were not affected. Unexpectedly, we discovered that TOFA acts through a non-canonical inhibition of protein S-acyltransferases. Protein S-acylation in AML cells specifically requires 16-to-18 carbon long fatty acids and is essential to maintain mitochondrial respiration upon glutaminolysis inhibition. Healthy cells in contrast have high intrinsic metabolic flexibility independent of S-acylation. Our results expose a unique mechanism of metabolic plasticity in cancer that could be targeted to enhance metabolic anti-cancer therapies.
    DOI:  https://doi.org/10.64898/2026.03.02.708949
  9. Leuk Res. 2026 Mar 15. pii: S0145-2126(26)00048-2. [Epub ahead of print]164 108204
    A real-world analysis of the impact of azole antifungal prophylaxis on outcomes in patients with newly diagnosed acute myeloid leukemia treated with venetoclax-based therapy.
    Alexander Ambinder, Mark Levis, Xin Wang, Keith Pratz, Andrew Matthews.
      In patients with acute myeloid leukemia (AML) receiving intensive chemotherapy (IC), antifungal prophylaxis (AFP) with mold-active azoles improves overall survival; however, the benefits of AFP in patients receiving venetoclax and a hypomethylating agent (Ven/HMA) remain unproven. Ven/HMA is associated with lower rates of invasive fungal infections but requires dose adjustment when combined with azole antifungals due to drug-drug interactions. We conducted a retrospective analysis of patients in a de-identified electronic health record database to determine the impact of AFP use in patients with newly diagnosed AML who received Ven/HMA on overall survival. Of the 1564 patients identified, 420 (26.9%) received AFP with an azole. There were no differences in age, sex, race, insurance status, socioeconomic status, eastern cooperative group (ECOG) performance status, blast percentage, de novo percentage, European LeukemiaNet (ELN) 2022 risk, high risk mutations (TP53, ASXL1, RUNX1), receipt of cytoreduction, or specific HMA agent used between the AFP and no AFP groups. Composite complete response rates were similar between groups, but AFP use was associated with higher rates of prolonged neutropenia. In multivariable analysis, patients who received azole AFP did not have improved survival (HR 1.29, 95% CI 1.10-1.53, P = .004) compared to patients who did not (median OS 10 months vs. 11 months), with similar lack of benefit across agents: voriconazole (HR 1.04, p = 0.75), fluconazole (HR 1.26, p = 0.039), isavuconazole (1.52, p = 0.048), and posaconazole (HR 1.62, p = 0.005). Routine azole AFP does not improve overall survival in patients receiving Ven/HMA, contrasting with proven benefits in intensive chemotherapy, likely due to lower fungal infection risk combined with the complexities of managing drug-drug interactions in routine practice, as evidenced by high rates of inadequate venetoclax dose adjustment in this cohort.
    Keywords:  Acute myeloid leukemia (AML); Antifungal prophylaxis; Invasive fungal infection; Outcomes; Real-world evidence; Venetoclax
    DOI:  https://doi.org/10.1016/j.leukres.2026.108204
  10. Leukemia. 2026 Mar 18.
    Targeting BMP and TAZ/TEAD mechanotransduction pathways impairs acute myeloid leukemia chemoresistance.
    Léa Barral, Nicolas Lespinasse, Camila Martin Cardozo, Sandrine Jeanpierre, Anna Bourgeois, Katharina Rösel, Emmanuel Beillard, Djohana Laurent, Pauline Peyrouze, Amine Belhabri, Yann Guillermin, Frederic Mazurier, Meyling Cheok, Marie-Charlotte Audry-Deschamps, Magalie Faivre, Véronique Maguer-Satta, Sylvain Lefort.
      Despite extensive research and intensive use of chemotherapies in clinics, the 5-year overall survival of acute myeloid leukemia (AML) patients does not exceed 20%. The clonal expansion of leukemic blasts leads to modifications of the bone marrow physical properties, including increased extracellular matrix stiffening, upregulation of intramedullary pressure and reduction of the space available for cells. These biomechanical modifications are speculated to alter therapeutic response and cause treatment resistance. To address this, we herein focused on the role of mechanotransduction pathways in AML. Analysis of primary AML samples or cell lines revealed that BMPR1B and TAZ/TEAD but not YAP levels were higher after patient relapse or in cells resistant to cytarabine or venetoclax. In addition, highly confined resident mesenchymal stem cells expressed higher levels of BMP4, which in turn specifically activated AML-resistant cells. In these cells, TAZ expression was associated with improved adhesion to microenvironmental components and increased intrinsic deformability. Finally, using a 3D human bone marrow-like model, we showed that targeting BMPR1B or TAZ/TEAD in combination with cytarabine impaired persistence of AML primary cells within the AML niche. Future therapeutic approaches could involve BMPR1B and/or TAZ/TEAD targeting in the context of AML patients refractory to chemotherapy or after relapse.
    DOI:  https://doi.org/10.1038/s41375-026-02904-7
  11. Hematol Oncol. 2026 Mar;44(2): e70180
    Preliminary Safety and Efficacy of Navitoclax Plus Ruxolitinib in Janus Kinase Inhibitor-Naïve Patients With Myelofibrosis From the Multicenter, Open-Label, Phase 2 Study (REFINE).
    Francesco Passamonti, James M Foran, Anand Tandra, Valerio De Stefano, Maria Laura Fox, Ahmad Mattour, Mary Frances McMullin, Andrew C Perkins, Gabriela Rodriguez-Macías, Hassan A Sibai, Akshanth R Polepally, Yan Sun, Avijeet S Chopra, Jason G Harb, Qin Qin, Jalaja Potluri, Jonathan How.
      Myelofibrosis is characterized by perturbation of the JAK/STAT pathway and upregulation of anti-apoptotic factors leading to myeloproliferation, bone marrow fibrosis (BMF), extramedullary hematopoiesis, splenomegaly, and cytopenias. Navitoclax, a potent oral B-cell lymphoma (BCL)-XL/BCL-2 inhibitor, promotes apoptosis of malignant myelofibrosis cells. Herein, we present results of Cohort 3 of the Phase 2 REFINE study (NCT03222609), which evaluated efficacy and safety of navitoclax plus ruxolitinib in JAKi-naïve patients with myelofibrosis. JAKi-naïve patients with primary or secondary myelofibrosis (≥ 18 years with splenomegaly, DIPSS intermediate-2 and high-risk myelofibrosis, and ECOG 0-2) and platelet count > 100 × 109/L were enrolled and treated with navitoclax 100 mg once daily (QD) or 200 mg QD according to platelet count (≤ 150 × 109/L or > 150 × 109/L, respectively). Ruxolitinib was given twice daily (dose per label). Primary endpoint: spleen volume reduction of ≥ 35% (SVR35) at week 24. Secondary endpoints: ≥ 50% reduction in total symptom score (TSS50) at week 24, change in grade of BMF, anemia response, and safety. Thirty-two patients received ≥ 1 dose of navitoclax plus ruxolitinib. Median (range) duration of follow-up was 44 months (5-58). 63% (20/32) of patients achieved SVR35 at week 24; median (range) time to first SVR35 was 12 weeks (11─48). Of 24 evaluable patients, 21% achieved ≥ 50% reduction in driver gene variant allele frequency (VAF). Of 27 evaluable patients, 11 (41%) achieved TSS50 at week 24; median (range) time to first TSS50 of 3 weeks (0─16). BMF improved from baseline by ≥ 1 grade in 13/27 patients (48%) at any time on study. Anemia response rates were 38% (5/13) for transfusion-independent and 100% (2/2) for transfusion-dependent patients. No bleeding events or deaths were attributed to navitoclax. These findings suggest navitoclax plus ruxolitinib has a tolerable safety profile and provides clinically meaningful improvements for JAKi-naïve patients with myelofibrosis. TRIAL REGISTRATION: NCT03222609.
    Keywords:  BCL‐2; clinical trials; hematological malignancy; myelofibrosis
    DOI:  https://doi.org/10.1002/hon.70180
  12. Cell Death Differ. 2026 Mar 17.
    Aberrant Kupffer-like differentiation of hematopoietic stem cell is critical for the MDS pathogenesis in Setd2-deficient mice.
    Jiachun Song, Fuhui Wang, Yinyin Xie, Xinyue Luo, Hong Tao, Rong Fan, Yan Zhou, Jing Wu, Ting Huang, Haifeng Zhao, Xiaojian Sun, Qiuhua Huang, Yuanliang Zhang.
      Histone methyltransferase SETD2 is recurrently mutated in hematopoietic malignancies. Our previous study showed that Setd2 deficiency impairs the self-renewal potential of murine hematopoietic stem cells (HSCs) and drives myelodysplastic syndrome (MDS)-like disorders. However, the precise oncogenic advantages conferred upon HSCs by Setd2 loss remain unclear. In this study, we found that Setd2 deficiency disrupted the fidelity of HSC lineage differentiation with preferential erythroid commitment and excessive macrophage priming, leading to ineffective erythropoiesis and the production of inflammatory embryonic-derived Kupffer cell (EmKC)-like cells. Notably, these EmKC-like cells exhibited HSC-independent self-renewal capability and remotely perturbed intramedullary hematopoiesis by inducing systemic inflammation. Furthermore, macrophage depletion effectively alleviated the inflammatory state and relieved MDS-like symptoms. Mechanistically, Setd2 loss leads to significant changes in DNA methylation and chromatin accessibility, resulting in the activation of Irf8. These findings suggest that the long-lived inflammatory cells may compensate for the HSC self-renewal defects, triggering systemic inflammation and driving hematopoietic malignant transformation. This paradigm provides a new understanding of hematopoietic malignancies with functional defects and exhaustion of HSCs.
    DOI:  https://doi.org/10.1038/s41418-026-01715-8
  13. Blood. 2026 Mar 18. pii: blood.2025031924. [Epub ahead of print]
    Inhibition of p300/CREBBP catalytic activity drives context-dependent transcriptional activation in AML.
    Markus Meyerhöfer, Yawen Zhou, Aaron Gallego-Crespo, Viral Shah, Malte Andreas Behrendt, Maria Saura-Pañella, Björn Häupl, Oleksandr Todoriuk, Monika Hartmann, Matthias Klein, Catherine Wölfel, Patricia S Hähnel, Christian S Michel, Sabine Muth, Thomas Kindler, Tobias Bopp, Hansjörg Schild, Sarah J Horton, Markus P Radsak, Matthias Theobald, George S Vassiliou, Brian Jp Huntly, Michael Wm Kühn, Falk Butter, Thomas Oellerich, Daniel Sasca.
      The lysine acetyltransferase (KAT) activity of p300/CREBBP has traditionally been linked to transcriptional activation. This has been attributed largely to acetylation of histone residues such as H3K27ac, a defining hallmark of active regulatory elements. Here we show that, in acute myeloid leukemia (AML), inhibition of p300/CREBBP catalysis can paradoxically increase transcription. We combined time-resolved dynamics of nascent and total transcription with chromatin binding dynamics of p300/CREBBP and their associated TFs/co-regulators (inferred from chromatin pull-down proteomics, acetyl-proteomics and motif enrichment) to uncover mechanisms of transcriptional rewiring after p300/CREBBP catalytic inhibition. In parallel, we dissected the functional contribution of individual p300/CREBBP acetyl-interactome members to KAT inhibition using genome-wide CRISPR-Cas9 dropout and focused Perturb-seq screens. Together, these approaches revealed that KAT inhibition paradoxically retains p300/CREBBP and promotes cooperative TF assembly and increased H3K27 acetylation at a subset of regulatory elements. The effect was most pronounced at IRF motif-enriched loci, including interferon-stimulated genes (ISGs), where KAT inhibition triggered p300/CREBBP accumulation and enhanced combinatorial TF binding, enabling recruitment of the ISG activator STAT1. Consequently, ISG loci were converted into transcriptionally active states that induced cell-cycle arrest, differentiation and apoptosis. Therapeutically, combining KAT inhibition with interferon-alpha augmented ISG expression, synergistically drove AML cell death in vitro and significantly extended survival in both AML xenografts and murine models. These findings refine our understanding of p300/CREBBP KAT activity, demonstrating that cooperative TF assembly can reconfigure p300/CREBBP-containing complexes under catalytic inhibition to induce transcription, with translational implications for reprogramming interferon-driven programs through catalytic inhibition in AML and beyond.
    DOI:  https://doi.org/10.1182/blood.2025031924
  14. Blood Adv. 2026 Mar 17. pii: bloodadvances.2025018695. [Epub ahead of print]
    Phase 1b study of ABBV-744, a novel, selective BET inhibitor, as monotherapy in patients with myelofibrosis.
    John O Mascarenhas, Laura Maria Fogliatto, Steven D Green, Ignacio Corvalan, Elie Traer, Keita Kirito, Hun S Chuah, Kazuki Sakatoku, Rasmus T Hoeg, Mohamad Khawandanah, David Lavie, Zoë Hunter, David Quinn, Yizhuo Wang, Jason G Harb, Jiuhong Zha, Uriel M Malyankar, Ellen K Ritchie.
      Janus kinase inhibitors (JAKi) are standard of care for patients with myelofibrosis (MF) but can be associated with treatment-limiting cytopenias and do not modify underlying disease. Novel treatments targeting other clinically relevant pathways are needed. Inhibitors of bromodomain (BD) and extra-terminal domain (BET) proteins are a promising class of drugs that have demonstrated the ability to modulate key pathways involved in inflammation, fibrosis, and apoptosis. ABBV-744 is a novel small molecule that targets the BDII domain of BET proteins and has previously been shown to be well tolerated when administered daily at doses of 120 mg and 180 mg to patients with acute myeloid leukemia. We report the outcomes of a multicenter, open-label phase 1b study of ABBV-744 in patients with MF who received 1 or more prior lines of therapy, including a JAKi. The primary objective was safety, including dose-limiting toxicities (DLTs). Secondary endpoints included a reduction in spleen volume of ≥35% (SVR35), ≥50% reduction in total symptom score (TSS50), objective response rate, and pharmacokinetics. All 21 patients experienced at least 1 treatment-emergent adverse event, and 11 patients experienced a DLT. The most common events leading to DLTs were thrombocytopenia (33%) and anemia (24%). SVR35 was attained in 24% of patients at Week 12 and 33% at Week 24. TSS50 was reported for 29% of patients at 12 weeks and 19% at Week 24. These outcomes are noteworthy in this heavily pretreated population considering the advanced disease state and limited treatment options for this patient population. (NCT04454658).
    DOI:  https://doi.org/10.1182/bloodadvances.2025018695
  15. Cell Rep Med. 2026 Mar 17. pii: S2666-3791(26)00103-5. [Epub ahead of print]7(3): 102686
    FBXO3-mediated DUSP9 ubiquitination promotes leukemia stem cell maintenance and tyrosine kinase inhibitor resistance in chronic myeloid leukemia.
    Xudong Li, Shiyu Zuo, Yanli Zhang, Zexing Liu, Na Shen, Qingqing Ma, Mingxia Sun, Binglei Zhang, Mengjia Li, Hong Huang, Mengya Gao, Zhenghua Huang, Huifang Zhao, Yilin Chen, Fengcai Gao, Wenjuan Fan, Zhen Zhang, Yuhan Hu, Yu An, Siyue Li, Miao Liu, Yupeng Liu, Yuxuan Liu, Chaoge Li, Yiguo Zhang, Yingmei Li, Weijie Cao, Fang Wang, Yongping Song, Linping Xu, Zhilei Bian, Wei Li.
      Eradicating leukemia stem cells (LSCs) and overcoming tyrosine kinase inhibitor (TKI) resistance is urgent for chronic myeloid leukemia (CML) treatment. We find that F-box protein 3 (FBXO3) is highly upregulated in CD34+ CML stem cells from TKI-resistant patients and identify it as an innovative CML-LSC marker via single-cell RNA sequencing (scRNA-seq). FBXO3 deficiency induces apoptosis and reduces proliferation of CML cell lines and LSCs in vitro and in vivo, with minimal effects on normal CD34+ hematopoietic stem cells (HSCs). Mechanistically, FBXO3 interacts with DUSP9 to promote its ubiquitination and activate the MAPK pathway, critical for CML cell activity. DUSP9 knockdown partially reverses FBXO3-deficiency-mediated LSC elimination. Furthermore, FBXO3 inhibitor monotherapy or combination with imatinib effectively eradicates CML-LSCs, overcomes TKI resistance, and spares normal hematopoiesis. Collectively, our findings highlight FBXO3's role in CML progression and support combining FBXO3 inhibitors with TKIs for durable LSC elimination.
    Keywords:  CML-LSCs; DUSP9; FBXO3; TKI resistance; chronic myeloid leukemia
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102686
  16. Blood. 2026 Mar 18. pii: blood.2025032569. [Epub ahead of print]
    Randomized trial of GvHD Prophylaxis in Haploidentical PBSC Transplantation: ATG, PTCy, and Low-Dose Combination Therapy.
    Jun Yang, Yannan Jia, Xiaoxia Hu, Fang Zhou, Xiong Ni, Jiangbo Wan, Yi Ding, Mei Kang, Xiaolin Yu, Chuanhe Jiang, Luxiang Wang, Liping Wan, Yu Cai, Chongmei Huang, Huiying Qiu, Xueying Ding, Yin Tong, Baoxia Dong, Kun Zhou, Xianmin Song.
      The optimal graft-versus-host disease (GvHD) prophylaxis strategy in haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) remains controversial. In this open-label, phase Ⅲ study, patients aged 14-70 years with acute myeloid leukemia or myelodysplastic syndromes with excess blasts Ⅰ or Ⅱ were randomized (2:1:1) to receive low-dose ATG (5 mg/kg)/PTCy (50 mg/kg), standard-dose ATG (total dose 10 mg/kg), or a PTCy (total dose 100 mg/kg)-based regimen for GvHD prophylaxis. The co-primary endpoints were the cumulative incidence (CI) of grade Ⅱ-Ⅳ acute GvHD (aGvHD) by day 100 and GvHD/relapse-free survival (GRFS) at 1 year post-transplant. A total of 407 patients were randomized to receive ATG/PTCy (185 patients), ATG (113 patients), or PTCy (109 patients) regimen for GvHD prophylaxis. By day +100, the CI of grade Ⅱ-Ⅳ aGvHD did not differ significantly among the three groups (P=0.210). Although the overall incidence of chronic GvHD (cGvHD) was comparable across all groups (P=0.110), the 2-year CI of moderate-to-severe cGvHD was numerically lower in the ATG/PTCy (17.4%) and ATG (17.3%) groups compared to the PTCy group (28.3%), without reaching statistical significance (P=0.095). No significant differences were observed in survival outcomes among the three groups. Notably, the cumulative incidence of neutrophil and platelet recovery was significantly higher in the ATG/PTCy group compared to the other groups (P<0.001). This trial suggested that the three GvHD prophylaxis strategies presented similar efficacy in preventing grade II-IV aGvHD and yielded comparable survival. This trial was registered at www.clinicaltrials.gov as NCT03608059.
    DOI:  https://doi.org/10.1182/blood.2025032569
  17. Nat Commun. 2026 Mar 18.
    Chromatin reorganization drives overexpression of a Btaf1 variant underpinning hematopoietic aging.
    Le Zong, Bongsoo Park, Yaqiang Cao, Fei Ma, Ferda Tekin-Turhan, Wakako Kuribayashi, Keji Zhao, Isabel Beerman.
      Age-associated hematopoietic stem cell (HSC) dysfunction is accompanied by dramatic transcription changes, but it remains unclear whether specific transcripts could orchestrate these HSC aging phenotypes. Here, we perform epigenetic profiling in male mice to investigate the regulatory mechanisms underlying the HSC aging transcriptome and screen for potential aging driver genes. We identify a looping structure formed between part of the Btaf1 gene and the whole Ide gene in old HSCs which is accompanied by overexpression of a shorter variant of Btaf1 (nBtaf1). Mechanistically, elevated expression of nBtaf1 drives the aging-associated overexpression of HSC and megakaryocyte progenitor (MkP) signature genes via regulating TBP binding at their promoters, which contributes to HSC expansion and elevated MkP production in aged mice. ShRNA-mediated knockdown of nBtaf1 restores a younger HSC transcriptome and specifically represses aging-associated HSC expansion and elevated MkP production. In summary, our data provide high resolution analysis of a dysregulated HSC aging epigenome and reveal a Btaf1 variant that drives HSC aging phenotypes in mice.
    DOI:  https://doi.org/10.1038/s41467-026-70787-4
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