bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2026–02–01
27 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Common variation at 1q23.3, 2p23.3, 2q33.3, and 2p21 influences risk of acute myeloid leukemia.
  2. Clonal hematopoiesis driver mutations: molecular mechanisms and clinical implications - inclusive fitness of pre-leukemic hematopoietic stem and progenitor cells through pro-inflammatory features of their progeny.
  3. Synthetic lethality of decitabine plus ATR inhibition for TP53-mutated AML.
  4. Baseline IPSS-M vs Pretransplant Risk Downstaging as Prognostic Determinants in MDS Undergoing Allogeneic Transplantation.
  5. Hypomethylating agents plus venetoclax versus intensive chemotherapy in acute myeloid leukemia with chromosome 5 and 7 abnormalities.
  6. Phf6 truncating mutation drives leukemogenesis via disrupted epigenetic regulation in mice.
  7. The LMO2-LDB1-TAL1 complex regulates transcription networks in acute myeloid leukemia.
  8. High-Dimensional Spatiotemporal Single-Cell Atlas and 3D imaging of Bone Marrow Microenvironment during CML Progression.
  9. GVHD and GRFS in patients with acute myeloid leukemia undergoing allogeneic HCT with treosulfan- versus reduced-intensity busulfan-based conditioning: a subgroup analysis of a randomized phase 3 trial.
  10. Epigenetic silencing and pharmacological inhibition of EIF5A2 foster venetoclax sensitivity in acute myeloid leukaemia.
  11. AML PATIENTS WITH WILDTYPE TP53 BUT DEFECTIVE TP53-MEDIATED APOPTOSIS HAVE A DISMAL SURVIVAL.
  12. Targeting Aurora Kinase A to Prevent GVHD and Relapse after Myeloablative Allogeneic Hematopoietic Cell Transplantation.
  13. Targeting MCL-1 and MAPK overcomes venetoclax resistance in FLT3-ITD-positive AML cells harbouring activating PTPN11 (SHP-2) mutations.
  14. GATA1 N-terminus coordinates metabolic reprogramming in erythropoiesis.
  15. Remodelling of the bone marrow vasculature induced by venetoclax and azacitidine damage.
  16. Incorporation of genomic determinants improves diagnostic accuracy of oligomonocytic chronic myelomonocytic leukemia.
  17. Non-invasive detection of bone marrow fibrosis in myeloproliferative neoplasms using cell-free RNA.
  18. Efficacy and safety of avapritinib in advanced systemic mastocytosis: 4-year follow-up of the PATHFINDER study.
  19. Pregnancy after Haematopoietic Stem Cell Transplant: an international multicentre study.
  20. Oncogenic SF3B1 mutations alter the splicing of mRNA noncoding regions to induce a novel therapeutic vulnerability.
  21. A Cellular and Transcriptomic Atlas of the Aged Mouse Hematopoietic System.
  22. Metformin does not significantly alter longitudinal dynamics of clonal hematopoiesis.
  23. circPCMTD1: A protein-coding circular RNA that regulates DNA damage response in BCR/ABL1-positive leukemias.
  24. DHCR7 drives AML development through the IL6/JAK2/STAT3 signalling pathway.
  25. Ropeginterferon alfa-2b has minimal transplacental passage and breastmilk secretion in pregnant MPN patients.
  26. The role of m6A RNA methyltransferase METTL3 in drug resistance mechanisms in acute myeloid leukemia.
  27. Unveiling relative lymphopenia and elevated monocyte-to-lymphocyte count as novel independent adverse prognostic factors in chronic myelomonocytic leukemia (CMML)-Proposal of the objective prognostic index for CMML (OPIC).
  1. Blood. 2026 Jan 29. pii: blood.2025031266. [Epub ahead of print]
    Common variation at 1q23.3, 2p23.3, 2q33.3, and 2p21 influences risk of acute myeloid leukemia.
    Diyanath Ranasinghe, Wei-Yu Lin, Sarah E Fordham, Abrar A Alharbi, Nicola J Sunter, Claire Elstob, Mohammed H Nahari, Yaobo Xu, Catherine Park, Eric Hungate, Anne Quante, Konstantin Strauch, Christian Gieger, Andrew D Skol, Thahira Rahman, Lara Sucheston-Campbell, Theresa Hahn, Alyssa Ione Clay-Gilmour, Gail L Jones, Helen J Marr, Graham H Jackson, Tobias Menne, Matthew Collin, Adam Ivey, Robert K Hills, Alan K Burnett, Nigel H Russell, Jude Fitzgibbon, Richard A Larson, Michelle M Le Beau, Wendy Stock, Olaf Heidenreich, Amir Enshaei, Dumni Gunasinghe, Zoë L Hawking, Holly S Heslop, Devi Nandana, Bingjing Di, Anna Plokhuta, Imogen T Brown, David J Allsup, Richard S Houlston, Andrew Collins, Paul Milne, Jean Norden, Anne M Dickinson, Beverley Clare Lendrem, Ann K Daly, Louise Palm, Kim Piechocki, Sally Jeffries, Martin Bornhäuser, Christoph Röllig, Heidi Altmann, Leo Ruhnke, Desiree Kunadt, Lisa Wagenführ, Heather J Cordell, Rebecca Darlay, Mette K Andersen, Maria Chiara Fontana, Giovanni Martinelli, Giovanni Marconi, Miguel Ángel Sanz, José Cervera, Ines Gomez-Segui, Thomas Cluzeau, Chimene Moreilhon, Sophie Raynaud, Heinz Sill, Maria Teresa Voso, Hervé Dombret, Meyling H Cheok, Claude Preudhomme, Rosemary E Gale, David C Linch, Julia Weisinger, Andras Masszi, Daniel Nowak, Wolf Karsten Hofmann, Amanda Frances Gilkes, Kimmo Porkka, Jelena D Milosevic Feenstra, Robert Kralovics, Junke Wang, Manja Meggendorfer, Torsten Haferlach, Szilvia Krizsán, Csaba Bödör, Brian L Parkin, Sami N Malek, Friedrich Stölzel, Kenan Onel, James M Allan.
      Acute myeloid leukemia (AML) is a complex hematological malignancy with multiple disease sub-groups defined by somatic mutations and heterogeneous outcomes. Although genome-wide association studies (GWAS) have identified a small number of common genetic variants influencing AML risk, the heritable component of this disease outside of familial susceptibility remains largely undefined. Here we perform a meta-analysis of four published GWAS plus two new GWAS, totalling 4710 AML cases and 12938 controls. We identify a new genome-wide significant risk locus for pan-AML at 2p23.3 (rs4665765; P=1.35x10-8; EFR3B, POMC, DNMT3A, DNAJC27) which also significantly associates with patient survival (P=6.09x10-3). Our analysis also identifies three new genome-wide significant risk loci for disease sub-groups, including AML with deletions of chromosome 5 and/or 7 at 1q23.3 (rs12078864; P=7.0x10-10; DUSP23) and cytogenetically complex AML at 2q33.3 (rs12988876; P=3.28x10-8; PARD3B) and 2p21 (rs79918355; P=1.60x10-9; EPCAM). We also investigated loci previously associated with risk of clonal hematopoiesis (CH) or clonal hematopoiesis of indeterminate potential (CHIP) and identified several variants associated with risk of AML. Our results further inform on AML etiology and demonstrate the existence of disease sub-group specific risk loci.
    DOI:  https://doi.org/10.1182/blood.2025031266
  2. Haematologica. 2026 Jan 29.
    Clonal hematopoiesis driver mutations: molecular mechanisms and clinical implications - inclusive fitness of pre-leukemic hematopoietic stem and progenitor cells through pro-inflammatory features of their progeny.
    Tal Bachrach, Adrian Duek, Liran I Shlush.
      Clonal hematopoiesis (CH) is driven by the age-associated expansion of hematopoietic stem and progenitor cells (HSPCs) that harbor somatic driver mutations; however, the mechanisms underlying their long-term persistence remain incompletely understood. This review frames CH through the lens of inclusive fitness, proposing that mutant pre-leukemic HSPCs enhance their evolutionary success not only through intrinsic self-renewal advantages, but also via indirect effects mediated by their differentiated progeny. We synthesize evidence showing that mutant immune cells promote inflammatory microenvironments that selectively impair wild-type HSCs while reinforcing mutant self-renewal, establishing self-sustaining feedback loops that shape clonal dynamics and systemic disease risk.
    DOI:  https://doi.org/10.3324/haematol.2025.287480
  3. Blood Adv. 2026 Jan 29. pii: bloodadvances.2025018369. [Epub ahead of print]
    Synthetic lethality of decitabine plus ATR inhibition for TP53-mutated AML.
    Jeremy T Baeten, Sumedha Agashe, Imene Tabet, Jack T Wooldridge, Amber Carter, Jamie N Butler, Christopher A Miller, Nichole M Helton, Annabel Quinet, Kimberly B Johansson, Yichan Yang, Geoffrey L Uy, Alessandro Vindigni, Daniel C Link.
      TP53 mutations are found in 10-15% of myeloid neoplasms and are associated with a dismal prognosis. Although hypomethylating agents, such as decitabine, are active in TP53-mutated myeloid neoplasms (TP53-MN), mutation clearance is rarely complete and nearly all patients relapse. Molecular determinants of response to hypomethylating agents in TP53-MN are poorly understood. Here, we show that decitabine induces replicative stress with decreased replication fork progression, induction of single-strand DNA breaks, and activation of the ATR pathway. Resolution of decitabine-induced replication stress is impaired in TP53-mutated acute myeloid leukemia (AML) cells, representing a potential therapeutic vulnerability. Indeed, the combination of decitabine and ATR inhibition (ATRi) induces synthetic lethality that is selective for TP53-AML and due, in part, to induction of mitotic catastrophe. Interestingly, this synergistic lethality was not observed with azacitidine or treatment with GSK3685032, a potent DNMT1 inhibitor, both of which produce a comparable level of global hypomethylation to decitabine. Treatment with decitabine and ATR inhibitor reduces leukemia burden and prolongs survival in in vivo mouse models of TP53-mutated AML. Collectively, these show that TP53 loss generates a selective vulnerability to decitabine-induced replication stress, with the combination of ATR inhibition and decitabine showing promise as a new therapeutic approach for TP53-MN.
    DOI:  https://doi.org/10.1182/bloodadvances.2025018369
  4. Blood Adv. 2026 Jan 26. pii: bloodadvances.2025018431. [Epub ahead of print]
    Baseline IPSS-M vs Pretransplant Risk Downstaging as Prognostic Determinants in MDS Undergoing Allogeneic Transplantation.
    Luis E Aguirre, Haesook T Kim, Hany Elmariah, Stacey M Frumm, Amar H Kelkar, Vincent T Ho, Mahasweta Gooptu, John Koreth, Roman M Shapiro, Rizwan Romee, Sarah Nikiforow, Joseph H Antin, Robert J Soiffer, Shai Shimony, Marlise R Luskin, Jacqueline S Garcia, Evan C Chen, Martha Wadleigh, Eric S Winer, Richard M Stone, Daniel J DeAngelo, Najla Al-Ali, David A Sallman, Andrew T Kuykendall, Kendra L Sweet, Jeffrey E Lancet, Eric Padron, Onyee Chan, Zhuoer Xie, Corey S Cutler, Rami S Komrokji, Maximilian F Stahl.
      Risk stratification in myelodysplastic syndromes (MDS) is essential for clinical decision-making, yet the optimal approach to estimate risk for patients undergoing allogeneic stem cell transplantation (alloHSCT) remains uncertain. Whether dynamic changes in risk between diagnosis and post-hypomethylating agent (HMA) therapy improve prognostic accuracy beyond baseline evaluation has not been established. We retrospectively studied 176 HMA-treated patients who underwent alloHSCT, applying the Molecular International Prognostic Scoring System (IPSS-M) at both diagnosis and pre-transplant. The primary endpoint was 4-year progression-free survival (PFS). Overall, dynamic assessment did not improve prognostic performance compared with baseline evaluation. For 4-year PFS, C-indices at diagnosis versus at alloHSCT were 0.6406 versus 0.6377 (p=0.82). Patients with worsening risk after HMA experienced notably inferior outcomes, while those with apparent improvement fared no better than patients with unchanged risk (4-year PFS: 50%, 50%, and 31% for improved, unchanged, and worsening risk, respectively). Apparent IPSS-M improvement before alloHSCT yielded no gains in survival and no reduction in relapse relative to unchanged risk, a pattern consistent among TP53 wild-type patients. Moreover, clearance of TP53 mutations following HMA therapy did not translate into improved post-transplant outcomes. In summary, dynamic reassessment with IPSS-M prior to alloHSCT offers no prognostic advantage over baseline evaluation at diagnosis in HMA-treated MDS patients. Accordingly, risk reduction should not be regarded as a therapeutic goal or trial endpoint, whereas risk progression constitutes an adverse marker that may inform incorporation of post-transplant maintenance strategies or intensified conditioning regimens to improve survival.
    DOI:  https://doi.org/10.1182/bloodadvances.2025018431
  5. Haematologica. 2026 Jan 29.
    Hypomethylating agents plus venetoclax versus intensive chemotherapy in acute myeloid leukemia with chromosome 5 and 7 abnormalities.
    Leora Boussi, Jan Philipp Bewersdorf, Yiwen Liu, Rory M Shallis, Luis E Aguirre, Rebecca P Bystrom, Andrius Zucenka, Sylvain Garciaz, Daniel J DeAngelo, Richard M Stone, Marlise R Luskin, Jacqueline S Garcia, Eric S Winer, Evan C Chen, Martha Wadleigh, Guillaume Berton, Kelly Ling, Amer M Zeidan, Eytan M Stein, Shai Shimony, Aaron D Goldberg, Maximilian Stahl.
      Abnormalities in chromosomes 5 and 7 are frequently identified in acute myeloid leukemia (AML), particularly enriched in therapy-and myelodysplasia-related disease, and confer an adverse prognosis. Given the high risk of relapse, allogeneic stem cell transplant (allo-SCT) is typically recommended for patients achieving complete remission (CR) following induction chemotherapy. We currently lack prospective data to decide whether intensive chemotherapy (IC) versus hypomethylating agent+venetoclax (HMA+ven) is the superior frontline treatment approach for these patients. Hence, we performed a retrospective study in a large cohort of patients with AML and deletion 7 (-7) and/or deletion 5 or 5q (-5/del5q) comparing outcomes between IC-versus HMA+ven-treated patients. Remission rates after IC and HMA+ven were found to be comparable (43% vs 52%, p=0.2). When adjusting for patient and disease characteristics in multivariable analysis (MVA), treatment with IC vs HMA+ven did not significantly impact overall survival (OS) (HR 1.02, p=0.9202), while age at diagnosis (HR 1.02, p=0.0324), prior myeloid disease (HR 1.42, p=0.0266), monosomal karyotype (HR 1.48, p=0.029), complex karyotype (HR 1.61, p=0.0156), and KRAS mutations (HR 2.21, p=0.0063) were associated with inferior survival. There was also no difference in OS in patients age 60-75 years by treatment strategy (7.8 vs 6.4 months, p=0.56), motivating future randomized trials of IC versus HMA+ven in this older population to inform optimal therapy. Importantly, OS was significantly improved in patients undergoing allo-SCT irrespective of frontline therapy, and allo-SCT consolidation was the most important predictor of long-term survival in MVA (HR 0.36, p.
    DOI:  https://doi.org/10.3324/haematol.2025.288891
  6. Leukemia. 2026 Jan 26.
    Phf6 truncating mutation drives leukemogenesis via disrupted epigenetic regulation in mice.
    Ying Guo, Pinpin Sui, Hui Yang, Ganqian Zhu, Ying Li, Shi Chen, Yuehui Zhao, Guo Ge, Yusra A Eisa, Caroline R Delma, Edward A Medina, Peng Zhang, Jihoon Lee, Mingjiang Xu, Feng-Chun Yang.
      Somatic mutations in PHF6 (PHD finger protein 6) are common in hematologic malignancies and confer worse overall survival in acute myeloid leukemia patients. These mutations are predominantly frameshift or nonsense variants, resulting in a truncated PHF6 protein. However, the specific role of truncated PHF6 in leukemogenesis remains unclear. Here, we generated a transgenic mouse model, Phf6R274XTg, expressing a patient-derived truncated Phf6 mutation specifically in hematopoietic lineages. Unlike Phf6 knock-out mice, which do not develop spontaneous diseases, Phf6R274XTg mice developed a spectrum of spontaneous hematologic malignancies that recapitulate key features of PHF6-mutated hematologic malignancies in patients. Expression of PHF6aa1-273 led to expansion of the hematopoietic stem cell/progenitor cell (HSC/HPC) pool and promoted myeloid-skewed differentiation. The Phf6R274X mutation also induced substantial transcriptional dysregulation in HSC/HPCs. Single-cell RNA-seq analysis revealed a unique HSC trajectory and enhanced myeloid-biased differentiation in Phf6R274XTg HSC/HPCs. Additionally, truncation of PHF6 altered genome-wide H3K27ac occupancy via enhanced activity of KAT6B acetyltransferase. Treatment with CTx-648, a KAT6A/KAT6B inhibitor, restored HSC function in Phf6R274XTg mice and prolonged the survival of leukemic Phf6R274XTg mice. These findings demonstrate a gain-of-function effect for truncated PHF6aa1-273 in driving leukemogenesis and highlight KAT6B as a promising therapeutic target in PHF6 truncation-associated hematologic malignancies.
    DOI:  https://doi.org/10.1038/s41375-025-02828-8
  7. Blood Neoplasia. 2026 Feb;3(1): 100186
    The LMO2-LDB1-TAL1 complex regulates transcription networks in acute myeloid leukemia.
    Nicholas Dunham, Zhenjia Wang, Yaseswini Neelamraju, Yan Guo, B Bishal Paudel, Cem Meydan, Jorge A Gandara, Fady A Abdelmalak, Hao Fan, Joyce Hardwick, Justin H Layer, Tak Lee, Bernhard Maier, W Hayes McDonald, Isaani Patnaik, Subhash Prajapati, Franck Rapaport, Caroline Sheridan, Gloria Sheynkman, Paul Zumbo, Michael W Becker, Lars Bullinger, Martin P Carroll, Richard J D'Andrea, Richard Dillon, Ross L Levine, Christopher E Mason, Ari M Melnick, Donna S Neuberg, Stefan Bekiranov, Chongzhi Zang, Utpal P Davé, Francine E Garrett-Bakelman.
      Relapsed acute myeloid leukemia (relAML) remains a clinical challenge. We have shown that epigenetic heterogeneity may contribute to transcriptional dysregulation and disease progression in AML, but the specific aberrant transcriptional programs have not been identified. We analyzed molecular profiles from patient-matched diagnostic and relapse AML specimens. A subset of differentially expressed genes (DEG) that were disparate in direction of expression change identified 2 patient subtypes. We predicted that transcriptional regulators (TR) might regulate the expression patterns observed. The expression patterns of the top TR predicted for the disparate genes associated with clinical outcomes. The top TR predicted for the disparate DEG and DEG identified in a patient-derived xenograft model of relAML included members of the LIM domain only 2 - LIM domain binding 1 - TAL BHLH TF1, erythroid differentiation factor (LMO2-LDB1-TAL1) multisubunit complex (LTMC). Analysis of DepMap data identified LMO2-dependent cells with a subset highly expressing TAL1, suggesting coordinated regulation. TAL1 copurified in immunoprecipitation for LMO2 and LDB1 followed by tandem mass spectrometry analysis in HEL and K562 cells, and results from chromatin immunoprecipitation experiments suggest significant co-occupancy of TAL1 and LDB1. Loss-of-function experiments targeting LMO2, LDB1, and TAL1 in AML cell lines associated with reduced cell growth, downregulation of cell cycle genes, and a negative association with gene expression patterns observed in relapsed patients with increased TAL1 expression. Our results from primary AML specimens and functional analyses of AML cell lines supports an essential role for the LTMC in AML. Targeting the complex or downstream effectors could provide novel therapeutic considerations for a subset of patients with AML.
    DOI:  https://doi.org/10.1016/j.bneo.2025.100186
  8. Blood. 2026 Jan 27. pii: blood.2025029824. [Epub ahead of print]
    High-Dimensional Spatiotemporal Single-Cell Atlas and 3D imaging of Bone Marrow Microenvironment during CML Progression.
    Lanzhu Li, Isabelle Rottmann, Borhan R Saeed, Geoff Ivison, Huan Wei, Jan Christian Schroeder, Gina Dunkel, Karen Greif, Yizheng Zhang, Ahmad Makky, Adrian Franz Ochsenbein, Carsten Riether, Yury Goltsev, Garry Nolan, Aaron T Mayer, Bettina Weigelin, Christian M Schürch.
      The bone marrow microenvironment (BMME) is essential for hematopoiesis and immunity, yet spatiotemporal single-cell analysis during leukemogenesis remains challenging. We characterized the BMME in femurs from wild-type and chronic myeloid leukemia (CML) mice at 7, 14 and 21 days post-induction by highly multiplexed and 3D microscopy. Using a 54-marker CODEX panel, we profiled 2,033,725 cells in 55 regions of interest and identified 41 cell-types. During CML progression, we observed myeloid and progenitor cell expansion, increased PD-L1+ leukemic cells, PD-1 upregulation on CD4+ and CD8+ T-cells, and a profound loss of B-cells, plasma cells and bone cells. Advanced CML exhibited a striking expansion of immature, pericyte-deficient vasculature that disrupted vascular niches and impaired hematopoietic stem/progenitor cell positioning. Spatial mapping revealed leukemia-specific cellular neighborhoods enriched in PD-1+CD8+ T-cells, suggesting localized immune exhaustion. Early CML showed increased contacts between plasmacytoid dendritic cells and megakaryocytes, whereas advanced CML featured heightened megakaryocyte emperipolesis of non-leukemic granulocytes. Megakaryocytes were morphologically irregular in CML mice and patient BM biopsies. In contrast, in mice with acute myeloid leukemia, vasculature and megakaryocytes were reduced, while remaining megakaryocytes retained normal morphology. Laser-capture microdissected megakaryocytes from newly diagnosed CML patients had reduced cytoskeleton gene expression, which was reversed in advanced cases treated with tyrosine kinase inhibitors. 3D imaging revealed vascular disorganization and depleted megakaryocytes in the diaphysis, underscoring region-specific pathology. Together, this study provides a spatiotemporal single-cell atlas of the BMME during leukemic progression, showing how leukemic cells reprogram it to support their expansion and immune evasion.
    DOI:  https://doi.org/10.1182/blood.2025029824
  9. Haematologica. 2026 Jan 29.
    GVHD and GRFS in patients with acute myeloid leukemia undergoing allogeneic HCT with treosulfan- versus reduced-intensity busulfan-based conditioning: a subgroup analysis of a randomized phase 3 trial.
    Friedrich Stölzel, Matthias Stelljes, Dietrich Wilhelm Beelen, Miroslaw Markiewicz, Péter Reményi, Thomas Luft, Fabio Ciceri, Eva-Maria Wagner-Drouet, Christian Junghanss, Christoph Scheid, Francesca Patriarca, Gerard Socié, Inken Hilgendorf, Alessandro Rambaldi, Kerstin Schaefer-Eckart, Domenico Russo, Gerald Wulf, Bertram Glass, Hélène Labussiere-Wallet, Gernot Stuhler, Maria Bieniaszewska, Jochen Casper, Ernst Holler, Fabio Benedetti, Anna Paola Iori, Desiree Kunadt, Jelena Mihajlović, Bettina Schild, Imran Khan, Xieran Li, Wolfgang Bethge.
      Acute myeloid leukemia (AML) is the most common indication for allogeneic hematopoietic cell transplantation (alloHCT), yet graft-versus-host disease (GVHD) remains a major post-transplant complication. Conditioning regimens, particularly reduced-intensity approaches, are critical in optimizing outcomes. This subgroup analysis of the phase 3 MC-FludT.14/L trial compared treosulfan-fludarabine with reduced-intensity busulfan-fludarabine in 352 AML patients (aged 31-70) undergoing alloHCT. The primary endpoint was 24-month event-free survival (EFS); secondary endpoints included overall survival (OS), GVHD incidence, relapse/progression, and non-relapse mortality (NRM). Treosulfan compared to busulfan demonstrated superiority: 24-month EFS was 65% vs. 53% (p = 0.01), and OS was 73% vs. 65%. EFS benefits were consistent across AML risk categories and notably higher in patients with hematopoietic cell transplantation comorbidity index >2 (62% vs. 42%, p = 0.02). Treosulfan also showed lower NRM and relapse rates. GVHD outcomes favored treosulfan, with a significantly lower incidence of extensive chronic GVHD at 24 months (15.1% vs. 28.1%, p = 0.01). GVHD-free and relapse-free survival was also improved (53% vs. 40%, p = 0.02). The safety profile was more favorable with treosulfan. These findings support treosulfan-fludarabine as a more effective and safer conditioning regimen than busulfan-fludarabine for AML patients undergoing alloHCT, particularly those at higher risk.
    DOI:  https://doi.org/10.3324/haematol.2025.288770
  10. Br J Haematol. 2026 Jan 28.
    Epigenetic silencing and pharmacological inhibition of EIF5A2 foster venetoclax sensitivity in acute myeloid leukaemia.
    Eva Crespo-García, Carlos Quero-Dotor, Aleix Noguera-Castells, Laia Sancho-Vila, Laura Martinez-Verbo, Manel Esteller.
      We show how the loss of activity of the translation initiation factor EIF5A2-either through gene hypermethylation or pharmacologic inhibition of its highly specific hypusine post-translational modification-induces venetoclax sensitivity in acute myeloid leukaemia (AML) cells.
    Keywords:  DNA methylation; Epigenetics; acute myeloid leukemia; venetoclax
    DOI:  https://doi.org/10.1111/bjh.70339
  11. JCI Insight. 2026 Jan 27. pii: e197261. [Epub ahead of print]
    AML PATIENTS WITH WILDTYPE TP53 BUT DEFECTIVE TP53-MEDIATED APOPTOSIS HAVE A DISMAL SURVIVAL.
    Josephine Dubois, Anthony Palmer, Darren King, Mohamed Rizk, Karan Bedi, Kerby A Shedden, Sami N Malek.
      The survival of patients with acute myelogenous leukemia (AML) carrying mutations in TP53 is dismal. We report the results of a detailed characterization of responses to treatment ex vivo with the MDM2 inhibitor MI219, a p53 protein stabilizer, in AML blasts from 165 patients focusing analyses on TP53 wildtype (WT) patients. In total 33% of AML were absolute resistant to MDM2 inhibitor induced apoptosis, of which 45% carried TP53 mutation and 55% were TP53 WT. We conducted array-based expression profiling of ten resistant and ten sensitive AML cases with WT TP53 status, respectively, at baseline and after 2h and 6h of MDM2 inhibitor treatment. While sensitive cases showed the induction of classical TP53 response genes, this was absent or attenuated in resistant cases. In addition, the sensitive and resistant AML samples at baseline profoundly differed in the expression of inflammation-related and mitochondrial genes. No TP53 mutated AML patient survived. The 4-year survival of AML with defective MDM2 inhibitor induced TP53-mediated apoptosis despite WT TP53 was dismal at 19% when NPM1 was co-mutated and 6% when NPM1 was WT. In summary, we identified prevalent multi-causal defects in TP53-mediated apoptosis in AML resulting in extremely poor patient survival.
    Keywords:  Apoptosis; Cell biology; Leukemias; Oncology; p53
    DOI:  https://doi.org/10.1172/jci.insight.197261
  12. Blood Adv. 2026 Jan 27. pii: bloodadvances.2025017360. [Epub ahead of print]
    Targeting Aurora Kinase A to Prevent GVHD and Relapse after Myeloablative Allogeneic Hematopoietic Cell Transplantation.
    Shernan G Holtan, Punita Grover, Kelly Walton, Najla El Jurdi, Victoria Quinones, Joseph E Maakaron, Mark B Juckett, Veronika Bachanova, Joshua H Hou, Stephanie A Terezakis, Thomas J Myers, Linda J Paradiso, Todd E DeFor, Qing Cao, Brian C Betts.
      The success of post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis has driven efforts to optimize partner therapies that balance GVHD and relapse prevention. We report phase I dose-finding results of PTCy, sirolimus (SIR), and VIC-1911, a selective oral Aurora kinase A (AURKA) inhibitor, following myeloablative allogeneic hematopoietic cell transplantation (alloHCT). Results from murine and in vitro studies informed the development of the novel drug combination. In the phase I trial (NCT05120570), patients aged 18-60 years received myeloablative conditioning, followed by, PTCy (50 mg/kg, days +3/+4), SIR (from day +5, target 8-12 ng/ml), and VIC-1911 (25, 50, or 75 mg BID, days +5 to +45). The primary endpoint was achieving <54% pH3ser10 expression in CD4+ T cells by day +21. Preclinical models show that combining SIR with AURKA inhibition suppresses signaling downstream of CD28, enhancing GVHD prevention while leveraging the anti-leukemia activity of AURKA inhibition. In the phase I trial, the optimal VIC-1911 dose achieving target pathway inhibition without dose-limiting toxicities was 75 mg BID. Clinical outcomes included no grade III-IV acute GVHD through day 180 (0%) and low rates of moderate/severe chronic GVHD (6%) and relapse (0%) through 1 year (5/16 received maintenance). The 1-year overall survival for this cohort was 94%.VIC-1911 at 75 mg BID, combined with PTCy and SIR, effectively suppresses AURKA activity, offering promising GVHD and relapse prevention with a favorable safety profile and promising early clinical outcomes.
    DOI:  https://doi.org/10.1182/bloodadvances.2025017360
  13. Br J Haematol. 2026 Jan 29.
    Targeting MCL-1 and MAPK overcomes venetoclax resistance in FLT3-ITD-positive AML cells harbouring activating PTPN11 (SHP-2) mutations.
    Maximilian Fleischmann, Ole Hansen, Diana Voigtländer, Julia Bechwar, Lenny-Joseph Schwietzer, Sanja Bahr, Ulf Schnetzke, Mike Fischer, Florian H Heidel, Tina M Schnöder, Jörg P Müller, Andreas Hochhaus, Sebastian Scholl.
      Venetoclax (VEN)-based therapies have improved the treatment of acute myeloid leukaemia (AML); however, the emergence of resistance remains a major limitation. Mutations in protein tyrosine phosphatase (PTP) non-receptor type 11 (PTPN11) and FMS like tyrosine kinase 3 with internal tandem duplication (FLT3-ITD) are common in resistant patients and are linked to activation of mitogen-activated protein kinase (MAPK) signalling and increased expression of anti-apoptotic proteins such as myeloid cell leukaemia 1 (MCL-1) and b-cell lymphoma-extra large (BCL(x)L). Murine Ba/F3 cells with different FLT3-ITD variants were lentiviral transduced to express either wild-type PTPN11 (Src-homology 2 containing PTP) or the activating PTPN11-E76K mutation. Cells were treated with VEN, the MCL-1 inhibitor S63845 and the mitogen-activated protein kinase (MEK) inhibitor trametinib (TRA), alone or in combination. Additionally, primary AML samples were examined for drug sensitivity and protein expression profiles. Cells expressing PTPN11-E76K showed marked resistance to VEN, coinciding with sustained extracellular signal-regulated kinase activation and elevated MCL-1 and BCL(x)L levels. Combining VEN with MCL-1 inhibition significantly increased apoptosis. Co-treatment with TRA provided substantial synergistic benefits while yielding a more modest benefit in PTPN11-E76K-mutant cells. Both PTPN11 and FLT3 mutations confer resistance in AML, making them key factors in identifying high-risk patients. The presented results highlight the role of MAPK-driven MCL-1 and BCL(x)L expression, which mediates VEN resistance. While dual inhibition of B-cell lymphoma 2 and MCL-1 is already effective, additional MEK inhibition may further improve outcomes in PTPN11-mutated AML.
    Keywords:   AML ; MAPK ; MCL‐1 ; resistance; venetoclax
    DOI:  https://doi.org/10.1111/bjh.70344
  14. Blood. 2026 Jan 26. pii: blood.2025030464. [Epub ahead of print]
    GATA1 N-terminus coordinates metabolic reprogramming in erythropoiesis.
    Te Ling, Lavanya Bezavada, Rashid Mehmood, Kevin Zhang, Anitria Cotton, Jeremy Chase Crawford, Hongjian Jin, Surbhi Sona, Lei Li, Yan Ju, Lei Han, Nana Liu, Tam Tran, Hieu Vu, Yan Jin, Jinbin Zhai, Shondra M Pruett-Miller, Senthil Velan Bhoopalan, Jian Xu, Min Ni, John D Crispino.
      Mutations in GATA1 that cause skipping of exon 2, which encodes the N-terminus, are associated with the myeloid leukemia of Down syndrome and Diamond-Blackfan anemia (DBA). To elucidate the molecular function of this N-terminal region, we employed single-cell RNA sequencing (scRNA-seq) on fetal liver cells from Gata1 mutant embryos that express only the short isoform of GATA1 (GATA1s) lacking the N-terminus of full-length GATA1 (GATA1FL). scRNA-seq revealed defects in erythropoiesis and aberrant upregulation of glycolytic genes, including PKM, which encodes pyruvate kinase to catalyze the final and irreversible step of glycolysis. Using precision nuclear run-on sequencing (PRO-seq) and cleavage under targets and release using nuclease (CUT&RUN) following acute GATA1 deletion in erythroid cells, we identified PKM as a direct target of GATA1. Substitution of GATA1FL with GATA1s induced histone lactylation at the PKM promoter, increased PKM expression and activity, and enhanced glycolytic flux in erythroid progenitors, without affecting mitochondrial respiration. Importantly, PKM expression is also significantly elevated in DBA patients with RPS19 mutations, which is associated with reduced levels of GATA1, further supporting a link between GATA1s-driven defective erythropoiesis and dysregulated glycolysis. Together, these findings reveal that GATA1 controls not only heme metabolism, but also glycolytic reprogramming.
    DOI:  https://doi.org/10.1182/blood.2025030464
  15. Blood. 2026 Jan 29. pii: blood.2025030055. [Epub ahead of print]
    Remodelling of the bone marrow vasculature induced by venetoclax and azacitidine damage.
    Steven Ngo, Giuseppe Alessandro D'Agostino, Despoina Papazoglou, Fatihah Mohamad Nor, Katja Finsterbusch, Khadidja Habel, Alessandra Ferrelli, Fernando Anjos-Afonso, Dominique Bonnet.
      The Bcl2 inhibitor venetoclax in combination with the hypomethylating agents azacitidine (ven/aza) has become increasingly utilized clinically for the treatment of many hematological malignancies. Whilst its effects on malignant cells have been extensively studied, its impact to the surrounding bone marrow microenvironment (BME) remains unexplored. In this study, we report that ven/aza therapy causes significant damage to the BME of mice. Comparatively high Bcl2 expression in the sinusoidal endothelial cell compartment (SEC) amongst all stromal subtypes, results in high sensitivity to ven/aza treatment, causing selective depletion of SECs and breakdown in cell-cell communication pathways in the endothelial cell (EC) network, leading to vascular leakiness in the BM. Furthermore, our detailed transcriptomic and imaging studies reveals significant downregulation of essential adhesion molecules in residual SECs, leading to significant defects in human hematopoietic stem/progenitor cell (HSPC) homing and engraftment of hematopoietic stem cells (HSCs) after ven/aza treatment. To conclude, our study showcases that maintaining SEC integrity in response to ven/aza therapy may play a key factor in achieving effective engraftment of donor derived HSCs.
    DOI:  https://doi.org/10.1182/blood.2025030055
  16. Blood Cancer Discov. 2026 Jan 26.
    Incorporation of genomic determinants improves diagnostic accuracy of oligomonocytic chronic myelomonocytic leukemia.
    Guillermo Montalban-Bravo, Chong Wu, Juan Jose Rodriguez-Sevilla, Yue Wei, Kelly S Chien, Ian Bouligny, Rashmi Kanagal-Shamanna, Ziyi Li, Anuya Natu, Mark Gurney, Alexandre Bazinet, Danielle Hammond, Alex Bataller, Gautam Borthakur, Nicholas J Short, Courtney D DiNardo, Tapan M Kadia, Farhad Ravandi, Naval Daver, Naveen Pemmaraju, Elias Jabbour, Ghayas C Issa, Sa A Wang, Keyur P Patel, Guilin Tang, L Jeffrey Medeiros, Terra L Lasho, Christy M Finke, Aref Al-Kali, Clifford M Csizmar, Hassan Alkhateeb, Naseema Gangat, Abhishek A Mangaonkar, David Roman-Bravo, Leonor Arenillas, Ayalew Tefferi, Hagop M Kantarjian, Guillermo Garcia-Manero, Xavier Calvo, Mrinal M Patnaik, Sanam Loghavi.
      Recent updates to monocyte count thresholds recognize oligomonocytic chronic myelomonocytic leukemia (OM-CMML) as an early form of CMML. However, the clinical validity of these changes remains uncertain without incorporating biological and genomic factors. In this study, we analyzed a cohort of 911 patients (249 with OM-CMML, 359 with overt CMML, and 303 with myelodysplastic syndromes) using unsupervised clustering to evaluate the role of genomic determinants in refining CMML diagnosis. Our findings show that CMML molecular signatures (biallelic TET2 mutations or SRSF2-TET2 co-mutations) are linked to a distinct transcriptome, monocytic bias, classical monocytosis, and higher risk of progression to overt CMML in OM-CMML cases. We developed a weighted genomic model and diagnostic workflow showing that combining genomic signatures with bone marrow monocyte frequencies in OM-CMML more accurately predicts progression to overt CMML. These findings support integrating genomic determinants, and our clinic-ready diagnostic workflow, into the CMML diagnostic framework to improve accuracy.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-25-0264
  17. iScience. 2026 Jan 16. 29(1): 114325
    Non-invasive detection of bone marrow fibrosis in myeloproliferative neoplasms using cell-free RNA.
    Mohamed Saad, Stijn N R Fuchs, Carmen Schalla, Katrin Götz, Jessica E Pritchard, Niclas Flosdorf, Adam Benabid, Hélène F E Gleitz, Nils Leimkühler, Aurélien Dugourd, Rebekka K Schneider.
      Myeloproliferative neoplasms (MPNs), particularly with myelofibrosis (MF), involve a disrupted perivascular hematopoietic niche, ultimately leading to bone marrow fibrosis. We asked if the transcriptome in cell-free RNA (cf-RNA) from the peripheral blood of patients with MPN (with JAK2V617F mutation) can detect bone marrow fibrosis. Transcriptomic profiling revealed significant gene expression changes correlating with reticulin fibrosis grades. Advanced reticulin fibrosis grades (2-3) showed upregulation of TGF-β pathways and extracellular matrix (ECM) remodeling markers, with decreased hematopoietic support. Grade 3 fibrosis was associated with increased proliferation signals and elevated inflammatory markers (S100A8/9). RUNX1 was identified as a key transcription factor in fibrosis, with its overexpression driving myofibroblast differentiation in mesenchymal stromal cells. IL-18 emerged as a critical inflammatory mediator, with elevated plasma levels correlating with the transformation to high-grade fibrosis (reticulin grades 2-3). Functional assays confirmed that the IL-18 stimulation of mesenchymal stromal cells induced fibrotic transformation, emphasizing its role as a biomarker and target.
    Keywords:  Cancer; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2025.114325
  18. Blood Adv. 2026 Jan 28. pii: bloodadvances.2025017519. [Epub ahead of print]
    Efficacy and safety of avapritinib in advanced systemic mastocytosis: 4-year follow-up of the PATHFINDER study.
    Jason Gotlib, Andreas Reiter, Deepti H Radia, Iván Álvarez-Twose, Michael W Deininger, Tracy I George, Jens P Panse, Andrzej Mital, Kristen M Pettit, Alessandro M Vannucchi, Uwe Platzbecker, Olivier Hermine, Amro Elshoury, Cristina Livideanu, Ruben A Mesa, Celalettin Ustun, Massimo Triggiani, Ingunn Dybedal, Joseph G Jurcic, Roberta Zanotti, Stephen T Oh, Abdulraheem Yacoub, Elizabeth O Hexner, Prithviraj Bose, Stephanie G Lee, Wolfgang R Sperr, Elizabeth A Griffiths, Matthew Butler, Johannes Lübke, Ilda Bidollari, Hui-Min Lin, Svetlana N Rylova, Saša Dimitrijević, Javier I Muñoz-González, Daniel J DeAngelo.
      Advanced systemic mastocytosis (AdvSM), a clonal hematologic neoplasm driven predominantly by D816V-mutant KIT, is often characterized by organ damage. Associated hematologic neoplasms (AHN; usually myeloid) are often present, leading to poor survival. We report on the oral, highly selective, potent KIT D816V inhibitor avapritinib (200-mg once-daily starting dose) with >4 years follow-up from the fully enrolled PATHFINDER (NCT03580655) study. Endpoints included overall response rate (ORR; primary), duration of response (DOR), progression-free survival (PFS), overall survival (OS), changes in objective biomarkers of disease, and safety (all secondary). Of 107 patients with AdvSM (including 71 [66%] with SM-AHN; overall population median follow-up: 49 months), 83 were response evaluable. ORR was 73% (95% confidence interval [95% CI], 63%-83%). Median DOR was 58 months, PFS 51 months, and OS 62 months. Disease progression occurred in 21/107 patients, predominantly in SM-AHN and largely driven by the AHN. Reductions in objective biomarkers of disease were observed. Most frequent (≥30% patients) treatment-emergent adverse events (TEAEs) (any grade; grade ≥3) were thrombocytopenia (58%; 31%); periorbital edema (57%; 6%), anemia (54%; 33%), peripheral edema (48%; 2%), and diarrhea (36%; 5%). Adverse events of special interest were cognitive effects (34%; 8%) and intracranial bleeds (4%, 2%). Eleven (10%) patients experienced TEAEs leading to death, of which 1 was deemed related to avapritinib by the principal investigator. With 4-year follow-up, avapritinib-treated patients with AdvSM experienced deep and durable responses and a favorable benefit-risk profile.
    DOI:  https://doi.org/10.1182/bloodadvances.2025017519
  19. Blood Adv. 2026 Jan 28. pii: bloodadvances.2025016977. [Epub ahead of print]
    Pregnancy after Haematopoietic Stem Cell Transplant: an international multicentre study.
    Nina Salooja, Dirk-Jan Eikema, David Michonneau, Andre A Tichelli, Jane F Apperley, Saad Akhtar, Jean Henri Bourhis, Johan A Maertens, Irfan Maghfoor, Claudia Massarotti, Matthew Collin, Stephan Mielke, Anna Maria Raiola, Michel Schaap, Petr Sedlacek, Gérard Socié, Steffie van der Werf, Mahmoud Aljurf, Krzysztof Kałwak, Grzegorz W Basak, Zinaida Peric, Olaf Penack, Hélène M Schoemans.
      Maintenance of fertility is important to patients undergoing haematopoietic stem cell transplant because many are of childbearing age and treatment is frequently sterilising. Pre-transplant fertility preservation counselling is currently limited by a paucity of data. Pregnancy post-transplant is an infrequent event and while small studies provide anecdotal information, interpretation of larger data sets can be confounded by lack of detail. In this multicentre study, patients transplanted between January 1995-December 2015 who subsequently became pregnant/partners became pregnant, were identified by centres registered with the European Society for Blood and Marrow Transplantation (EBMT). The association of pregnancy with underlying condition, transplant type and conditioning protocols was evaluated using robust data sets from the EBMT registry. The role of assisted reproductive techniques (ART) in pregnancy were also investigated and pregnancy outcomes described. From a data set of 54,323 transplanted patients, there were 621 pregnancies among 419 patients/partners, and 581 live births. There was substantial variation in likelihood of pregnancy following different conditioning protocols with highest rates in women observed after reduced intensity conditioning (RIC). ART were used by 33% of females and 56% of partners of male patients, with highest use following allografts using total body irradiation and lowest following RIC. Among females, pregnancy was more frequently associated with donor eggs than the use of their own stored eggs, embryos or tissue. Widespread use of ART distorts the association between pregnancies post-transplant and preservation of gonadal function, however our data highlight multiple factors relevant to contemporary pre-transplant counselling and fertility preservation services.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016977
  20. Blood. 2026 Jan 26. pii: blood.2025029972. [Epub ahead of print]
    Oncogenic SF3B1 mutations alter the splicing of mRNA noncoding regions to induce a novel therapeutic vulnerability.
    Michal Sekrecki, Agata Sekrecka, Rohan R Lattupally, Kenny Le, Xiaokang Jin, Chen Mozes, Brendan G Dwyer, Zhe Zhuang, Bryan A Romero, Jose Mario Bello Pineda, Xunhong Cao, Linh Nguyen, Vicky W Chen, Crystal Zhou, Jared A Wallace, Kailee L Tanaka, Charu Tiwari, Austin Gabel, Won Jun Kim, Robert F Stanley, Salima Benbarche, Jaspreet Thind, Abhinaya Muruganandham, Tian Yi Yi Zhang, Peter L Greenberg, Jason Gotlib, Gabriel N Mannis, William Shomali, Giselle Ghazal Salmasi, Calvin J Kuo, Tait D Shanafelt, Irtisha Singh, Daichi Inoue, Finn K Hansen, Nathanael S Gray, Capucine Van Rechem, Bita Fakhri, Xiaoyu Zhang, Sydney X Lu.
      Oncogenic mutations of SF3B1 are common in myeloid cancers, chronic lymphocytic leukemia (CLL) and select solid tumors. Their mechanistic basis for promoting oncogenesis has been investigated in detail, with the stereotyped missplicing of mRNA protein coding sequences most intensively studied. These changes, in genes such as MAP3K7, BRD9, and ABCB7, typically lead to loss-of-function, thus contributing to cancer pathogenesis.Here we systematically analyzed the impact of mutant SF3B1 on non-coding regions of mRNA transcripts across disease types, in both cell lines and primary patient specimens. This identified numerous novel and highly reproducible splicing alterations in such regions. Studies of one target gene, DCAF16, revealed multiple complex mutation-induced alterations in its 5' and 3' untranslated regions (5', 3' UTRs). Remarkably, these were mechanistically associated with increased DCAF16 protein levels in SF3B1 mutant cells, representing the first time that oncogenic SF3B1 has been shown to increase levels of a target protein in a gain-of-function manner. DCAF16 is a substrate recognition adapter for the DDB1/CUL4 E3 ubiquitin ligase complex. Novel protein degrader small molecules which co-opt DCAF16 to degrade BRD4 as a neosubstrate demonstrated preferential selectivity for SF3B1 mutant cancers and CLL primary patient specimens due to increased DCAF16 protein levels. In turn, this reveals the therapeutic relevance of mutant SF3B1 dysregulation of transcript untranslated regions and uncovers a novel strategy for the treatment of these important neoplasms.
    DOI:  https://doi.org/10.1182/blood.2025029972
  21. Aging Cell. 2026 Feb;25(2): e70394
    A Cellular and Transcriptomic Atlas of the Aged Mouse Hematopoietic System.
    Ryan R White, Kun Xiong, Matthew Wakai, Allison Surian, Christina Adler, Nicole Negron, Min Ni, Tea Shavlakadze, Yu Bai, David J Glass.
      Aging is a dominant risk factor for chronic diseases characterized by the functional decline of tissues and organs. During aging, the hematopoietic system declines in regenerative capacity-seemingly attributable to increases in DNA damage, replicative stress, and autophagic flux-resulting in skewing towards a myeloid lineage and away from a lymphoid lineage. Here, we characterized the transcriptomic and cellular landscape of the aged C57Bl/6J mouse hematopoietic system using a combination of bulk RNAseq and single cell RNAseq (scRNAseq). We show that aging leads to global transcriptional alterations in bulk peripheral blood mononuclear cells (PBMCs), lineage marker-depleted bone marrow cells (Lin-BM), and in hematopoietic stem and progenitor cells (HSPCs), immunophenotypically lineage marker negative (Lin-) Sca1+ cKit+ (LSK+). These changes indicate widespread activation of inflammatory processes, namely in PBMCs and Lin-BM cells. Interestingly, there is also a downregulation of cell cycle genes in HSPCs during aging. ScRNAseq across 39 hematopoietic cell types revealed age-related skewing in cell composition. Aged PBMCs showed significant decreases in CD4 and CD8 naïve cells concomitant with increases in CD4/8 memory and CD8 exhausted T cell populations. Lin-BM cells showed significant myeloid skewing in common myeloid progenitor (CMP) cells, as well as in the HSC population. We also identified a unique HSC population marked by increased Vwf, Wwtr1, and Clca3a1 expression that does not exist in young HSCs, thus likely marking true aged HSCs. Collectively, this work should serve as a useful resource for understanding and therapeutically targeting the aged hematopoietic system.
    DOI:  https://doi.org/10.1111/acel.70394
  22. Clin Cancer Res. 2026 Jan 28.
    Metformin does not significantly alter longitudinal dynamics of clonal hematopoiesis.
    Eshani Pareek, Yash Pershad, Kun Zhao, Md Mesbah Uddin, Liying Xue, Caitlyn Vlasschaert, Taralynn M Mack, Jeffrey Haessler, Jason M Collins, Elena Glick, Veronica Glaser, Rachel Heise, Wodan Ling, Bernhard Haring, Aladdin Shadyab, Hind Beydoun, Robert Wallace, Siddhartha Jaiswal, JoAnn E Manson, Pradeep Natarajan, Michael C Honigberg, Charles Kooperberg, Eric A Whitsel, Jacob O Kitzman, Alexander G Bick, Alexander R Reiner, Pinkal Desai.
       PURPOSE: Early intervention in patients with Clonal Hematopoiesis (CH) is an area of intense investigation with no currently approved agents. With recent mechanistic data on metformin as a possible therapeutic agent in CH and its availability in clinical practice, we sought to investigate clonal dynamics of CH mutations in metformin users.
    EXPERIMENTAL DESIGN: We analyzed longitudinal targeted deep sequencing of 1,104 CH mutations in 863 metformin-treated type 2 diabetic participants in two longitudinal cohorts: WHI and BioVu with blood collected at a median of 15.8 and 6.1 years apart respectively.
    RESULTS: Metformin duration (per 6 months) was not significantly associated with overall CH growth rate in WHI (β = -0.05%/year; 95% confidence interval (CI): -0.11 to 0.01; P = 0.08; N = 543) and in BioVU (β = -0.09%/year; 95% CI: -0.22 to 0.05; P = 0.20; N = 561) . Inverse-variance weighted random-effect meta-analysis demonstrated a small, statistically significant association (β = -0.06%/year; 95% CI: -0.11 to -0.002; P = 0.04; N = 1,104) without significant heterogeneity (P = 0.60). These results were similar when only considering DNMT3A and DNMT3A R882 clones.
    CONCLUSIONS: In our cohorts, duration of metformin use among diabetic users was associated with a small reduction in CH growth rate (-0.06%/year), which is modest compared to typical DNMT3A clonal growth rates of 5-7% annually. Metformin's clinical utility for modulating clonal dynamics in real-world settings appear limited and its clinical use for this indication requires further investigation in prospective studies.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-3606
  23. Blood. 2026 Jan 29. pii: blood.2025031129. [Epub ahead of print]
    circPCMTD1: A protein-coding circular RNA that regulates DNA damage response in BCR/ABL1-positive leukemias.
    Dimitrios Papaioannou, Amog P Urs, Rémi Buisson, Andreas Petri, Mingjun Liu, Lauren Woodward, Rohan Kulkarni, Xenia Weislämle, Olha Ivashkiv, Deedra Nicolet, Chinmayee Goda, Varvara Paraskevopoulou, Yaphet Bustos, Krzysztof Mrózek, Ann-Kathrin Eisfeld, Mahesh B Chandrasekharan, Gregory K Behbehani, Sakari Kauppinen, Iannis Aifantis, Guramrit Singh, Adrienne M Dorrance, Ramiro Garzon.
      Circular RNAs are a novel class of RNA transcripts, which regulate important cellular functions in health and disease. Herein, we report on the functional relevance of circPCMTD1 in BCR/ABL1-positive myeloid leukemias. In screening experiments, we found that circPCMTD1 depletion strongly inhibited the proliferative capacity of leukemic cells with BCR/ABL1 translocations. RNA sequencing and mass cytometry experiments identified aberrant activation of the DNA damage response (DDR) pathway as a downstream effect of circPCMTD1 depletion. DNA fiber assays, Comet assays and profiling of DDR markers (phospho-H2AX, phospho-CHK1, etc.) further underscored the pronounced effect of circPCMTD1 depletion in increasing genotoxic stress and inhibiting leukemic cell growth. circPCMTD1 targeting also led to aberrant DDR activation in leukemia patient blasts with BCR/ABL1 translocations. In in vivo experiments, circPCMTD1 knock-down prolonged the survival of mice engrafted with BCR/ABL1-positive leukemia cells. Mechanistically, we found that circPCMTD1 is enriched in the cytoplasm and associates with the ribosomes of leukemic blasts. We detected a cryptic open reading frame within the circPCMTD1 sequence and found that circPCMTD1 generates a 127 amino-acid peptide product (cPCMTD1-127aa). Using a custom-produced antibody, we found that the cPCMTD1-127aa interacts with the BCR/ABL1 oncoprotein, as well as with the BLM, TOP3A and RMI1 proteins, which form the BTR complex and regulate DNA repair and genome stability. cPCMTD1-127aa enhanced BTR complex formation, thereby increasing cellular tolerance to genotoxic stress. In summary, we identify and characterize circPCMTD1 as a molecular vulnerability and potential therapeutic target in BCR/ABL1-positive leukemias.
    DOI:  https://doi.org/10.1182/blood.2025031129
  24. Br J Haematol. 2026 Jan 29.
    DHCR7 drives AML development through the IL6/JAK2/STAT3 signalling pathway.
    Xu Dai, Zhaoxing Wu, Wenjing Zhang, Sirui Chen, Xiaoying Zhao, Yinan Lu, Yajing Ma, Weiwei Zheng.
      Acute myeloid leukaemia (AML) is a highly heterogeneous haematological malignancy defined by the abnormal proliferation of immature myeloid cells within the bone marrow. 7-Dehydrocholesterol reductase (DHCR7), a key enzyme in cholesterol metabolism, has been characterized as an oncoprotein in multiple cancer types, yet its functional relevance and underlying mechanisms in AML remain incompletely elucidated. The present study systematically investigated the biological role of DHCR7 in AML pathogenesis. In vitro functional assays demonstrated that either DHCR7 knockdown or treatment with the targeted inhibitor tamoxifen significantly suppressed AML cell proliferation. These inhibitory effects were accompanied by reduced intracellular cholesterol levels, accumulation of 7-dehydrocholesterol (7-DHC) and induction of endoplasmic reticulum stress, which ultimately triggered cellular apoptosis. Consistent with in vitro findings, both DHCR7 knockdown and intraperitoneal administration of tamoxifen markedly inhibited leukaemia progression in NSG (NOD Scid Gamma) mouse models, as validated by decreased bioluminescence intensity and reduced Ki-67 positivity. Mechanistic investigations further revealed that DHCR7 exerts pro-leukaemic effects through activation of the IL-6/JAK2/STAT3 signalling axis. Collectively, this study establishes the novel function of DHCR7 in AML pathogenesis and provides robust evidence supporting its potential as a therapeutic target for AML.
    Keywords:   DHCR7 ; 7‐DHC; AML; IL6/JAK2/STAT3; tamoxifen
    DOI:  https://doi.org/10.1111/bjh.70346
  25. Blood Adv. 2026 Jan 26. pii: bloodadvances.2025018811. [Epub ahead of print]
    Ropeginterferon alfa-2b has minimal transplacental passage and breastmilk secretion in pregnant MPN patients.
    Tsewang Tashi, Lee-Yung Shih, Yi-Te Yo, Amy Sullivan, Ho-Yen Chueh, Ming-Chung Kuo, Amanda Smith, Soo Jin Kim, Brynn Parsegov, Brandi N Reeves, Jihyun Song, Josef T Prchal.
      Pregnancy in patients with myeloproliferative neoplasms (MPNs) poses unique challenges due to increased risks of maternal complications and adverse fetal outcomes. Interferon-alpha (IFN-α) has been shown to be safe and is the preferred cytoreductive agent in pregnant MPN patients. Ropeginterferon alfa-2b (RopegIFN) is a novel monopegylated interferon and is the only IFN approved for the treatment of polycythemia vera (PV), but also used for essential thrombocythemia (ET) and myelofibrosis; yet, limited data exist on the safety of RopegIFN during pregnancy and lactation. In this study, we report four cases of pregnant MPN patients treated with RopegIFN, in whom maternal blood, umbilical cord blood, and breast milk samples were analyzed to assess exposure to RopegIFN. Quantitative ELISA and dot-blot assays demonstrated therapeutic levels of RopegIFN in maternal plasma but negligible levels in cord blood and breast milk, suggesting minimal transplacental transfer and excretion into breast milk. This is the first study to provide pharmacokinetic evidence of RopegIFN exposure during pregnancy and lactation. These findings support the safety of RopegIFN use in pregnant ET and PV patients and highlight the need for a collaborative registry to collect real-world data and guide management for this high-risk population.
    DOI:  https://doi.org/10.1182/bloodadvances.2025018811
  26. Blood Res. 2026 Jan 30. 61(1): 7
    The role of m6A RNA methyltransferase METTL3 in drug resistance mechanisms in acute myeloid leukemia.
    Suresh Prajapati, Charmi Jyotishi, Mansi Patel, Reeshu Gupta.
      This review examines the role of METTL3, a core RNA methyltransferase, in therapeutic resistance in acute myeloid leukemia (AML) and discusses emerging strategies to address this challenge. METTL3 regulates N6-methyladenosine (m6A) modifications on transcripts involved in key cellular processes, including apoptosis (BCL2, MCL1), metabolism (PGC-1α, CSRP1), proliferation (MYC), autophagy (FOXO3), and bone marrow microenvironmental interactions (ITGA4, AKT1). These modifications enhance the stability and translation of resistance-associated genes, supporting leukemic cell survival under treatment pressure. Pharmacological targeting of METTL3 has shown efficacy in preclinical AML models. Inhibitors such as STM2457, METTL3-directed PROTACs, and rational drug combinations with agents including venetoclax, anthracyclines, and ATRA, have reversed resistance phenotypes and impaired leukemic cell fitness. Beyond canonical resistance mechanisms, METTL3 also regulates noncoding RNAs, autophagy, and metabolic-epigenetic crosstalk, including histone lactylation, linking epitranscriptomic regulation to broader resistance pathways. By integrating molecular, cellular, and microenvironmental evidence, this review underscores METTL3 as a central driver of drug resistance and a promising therapeutic target in relapsed or refractory AML. Unlike previous summaries, it highlights the convergence of METTL3-mediated m6A modifications with noncoding RNA regulation, autophagy, and niche adaptation, and critically evaluates emerging therapeutic approaches, including catalytic inhibitors, PROTACs, and natural compounds.
    Keywords:  Acute Myeloid Leukemia; Drug resistance; METTL3; PROTACs
    DOI:  https://doi.org/10.1007/s44313-026-00123-8
  27. Hemasphere. 2026 Jan;10(1): e70286
    Unveiling relative lymphopenia and elevated monocyte-to-lymphocyte count as novel independent adverse prognostic factors in chronic myelomonocytic leukemia (CMML)-Proposal of the objective prognostic index for CMML (OPIC).
    Xavier Calvo, Abora Rial-Villavecchia, David Roman-Bravo, Sara Garcia-Avila, Lucia Gomez-Perez, Marta Salido, Anna Puiggros, Blanca Espinet, Concepcion Fernandez-Rodriguez, Barbara Tazon-Vega, Beatriz Bellosillo, Sandra Castaño-Díez, Marina Díaz-Beyá, Jordi Esteve, Carmen Lome, Lluis Colomo, Lourdes Florensa, Ana Ferrer Del Álamo, Juan Jose Rodriguez-Sevilla, Leonor Arenillas.
      Chronic myelomonocytic leukemia (CMML) shows marked prognostic heterogeneity. Although leukocytosis is a recognized adverse prognostic factor, the contribution of its individual components remains insufficiently defined. In a cohort of 240 patients classified according to International Consensus Classification (ICC) and World Health Organization (WHO) 2022 criteria-including 23% with oligomonocytic CMML-we evaluated the prognostic impact of neutrophil and monocyte percentage, along with surrogate markers of their relative increase, including relative lymphopenia (<20%) and elevated monocyte-to-lymphocyte ratio (MLR > 1). Both relative lymphopenia and MLR > 1 emerged as independent adverse prognostic factors, correlating with adverse mutations (TP53, RAS pathway) and high-risk clinical features. Notably, MLR > 1 identified a subset of patients with dysplastic CMML with molecular and clinical profiles resembling proliferative CMML (MP-CMML). These variables retained their prognostic impact after adjustment for established prognostic models (CMML-specific prognostic scoring system [CPSS], CPSS with the addition of the variable platelet < 100 × 10⁹/L [CPSS-P], and Mayo prognostic model), and their addition improved predictive performance. Based on these and other objective variables readily available from a routine complete blood count (CBC), we developed the objective prognostic index for CMML (OPIC), which integrates hemoglobin < 11 g/dL, platelets < 100 × 10⁹/L, MP-CMML, and MLR > 1. OPIC stratified patients into four risk categories with distinct survival outcomes (median overall survival [OS]: 104, 66.6, 34.3, and 18.3 months), demonstrating strong discriminatory power. Variable selection was performed using stepwise and elastic net regression, and random survival forests. Model performance metrics, including the C-index, time-dependent area under the receiver operating characteristic curve, and the Brier Score, were internally validated using bootstrapping-based resampling methods and externally validated in a cohort of 250 patients. OPIC provides a robust, accessible tool for CMML risk stratification, supporting its integration into routine clinical workflows and early therapeutic decision-making.
    DOI:  https://doi.org/10.1002/hem3.70286
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