bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2026–01–11
thirty-two papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Spectrum, prevalence, and clinical correlates of PPM1D mutations in patients with clonal hematopoiesis and clonal cytopenias.
  2. Long-Term Outcomes of Stem Cell Transplant in Older Patients With Acute Myeloid Leukemia Treated With Venetoclax-Based Therapies.
  3. Bone marrow failure, somatic rescue by p53 inactivation, and enhanced leukemogenesis in germline ERCC6L2 disease.
  4. Clinical outcomes of venetoclax combined with hypomethylating agents versus hypomethylating agents alone in TP53-mutated myelodysplastic syndromes.
  5. A Druggable Tumor Suppressor and Leukemic Stem Cell Marker.
  6. Impact of European LeukemiaNet-guided postremission therapy on outcomes of patients with AML from 2010 to 2022.
  7. Post-FDA Approval Experience With Momelotinib in JAK Inhibitor-Naïve Myelofibrosis: Focus on Anemia Response and Treatment-Emergent Nephropathy and Peripheral Neuropathy.
  8. Phase 3 study of intensive chemotherapy with or without dasatinib in core-binding factor acute myeloid leukemia.
  9. Triple-negative primary myelofibrosis: a comparative analysis of phenotype, genotype, and outcome.
  10. ΔNp73 isoform defines a TP53-mutant-like poor-risk subgroup of acute myeloid leukemia.
  11. Clonal Hematopoiesis and Lymphoma-Associated Mutations in Hematopoietic Progenitors in B-Cell Non-Hodgkin Lymphoma.
  12. Navigating prognostic stratification and approach to TP53-mutated myeloid neoplasms.
  13. Hematologic Landscape of Adult Patients With Diamond-Blackfan Anemia Syndrome.
  14. CK2 inhibitor, CX-4945, enhances BH3 priming and promotes apoptosis of venetoclax-resistant AML by targeting antiapoptotic proteins.
  15. Randomized Comparison of Cardiotoxicity With 60 Versus 90 mg Daunorubicin in AML Induction Therapy.
  16. Safety of gemtuzumab ozogamicin with cytarabine, daunorubicin, and midostaurin induction in FLT3-mutated AML.
  17. The Nicotinamide Salvage Pathway is a Metabolic Vulnerability of High-Risk MDS Stem Cells.
  18. Identifying targeted therapies for CBFA2T3::GLIS2 acute myeloid leukemia.
  19. Impact of Statin Use on Cardiovascular and Hematologic Outcomes Among Patients with Myeloproliferative Neoplasms.
  20. Nat10-mediated ac4C epitranscriptomics orchestrates hematopoietic stem/progenitor cell fate determination via translation control.
  21. Analysis of Patients With Monocytic and Monocytic-Like Acute Myeloid Leukemia, Including AML-M4 and AML-M5, Treated With Venetoclax Plus Azacitidine.
  22. Clonal Hematopoiesis of Indeterminate Potential and Clonal Cytopenias of Undetermined Significance: 2026 Update on Clinical Associations and Management Recommendations.
  23. Inflammageing and clonal haematopoiesis interplay and their impact on human disease.
  24. Scaffolding-dependent CASP1 constrains excessive cell-intrinsic inflammatory signaling in leukemia.
  25. Gastrin for the treatment of acute graft-versus-host disease of the stomach.
  26. Identification of a Musashi2 translocation as a novel oncogene in myeloid leukemia.
  27. NUP98 rearrangements in adult AML patients: evaluation of clinical implications and identification of novel fusion partners.
  28. Structural and Functional Analysis of GGPPS Inhibition as a Therapeutic Mechanism for Acute Myeloid Leukemia (AML).
  29. ATGL suppresses ferroptosis in acute myeloid leukemia cells by modulating the CEBPα/SCD1 axis and induces gilteritinib resistance.
  30. Prognostic value of BTG1 for predicting decitabine sensitivity in de novo acute myeloid leukemia.
  31. Sequential BCR::ABL1 evaluation during dose de-escalation in peripheral blood is more predictive of TFR success than single assessment at dose de-escalation in either peripheral blood or bone marrow.
  32. Next-Generation JAK Inhibitors in the Treatment of Myeloproliferative Neoplasms.
  1. Blood Adv. 2026 Jan 07. pii: bloodadvances.2025018031. [Epub ahead of print]
    Spectrum, prevalence, and clinical correlates of PPM1D mutations in patients with clonal hematopoiesis and clonal cytopenias.
    Talha Badar, Ludovica Marando, Eric Latorre-Crespo, Terra L Lasho, Francyess Denis Oliva, Chenyu Lin, Benjamin J McCormick, Mobachir El Kettani, Kashish Shah, Yael N Kusne, Omer Jamy, Kendall Diebold, Alexander Coltoff, Christy M Finke, James M Foran, Mohamed A Kharfan-Dabaja, Yao-Shan Fan, Liuyan Jiang, Rong He, Miles Thomas, Anand A Patel, David S Viswanatha, Mithun Vinod Shah, Antoine N Saliba, Abhishek A Mangaonkar, Kristina Kirschner, Aref Al-Kali, Naseema Gangat, Mark R Litzow, Mrinal M Patnaik.
      TP53 and PPM1D are key regulators of DNA damage response and repair and somatic mutations in these genes often co-occur in hematopoietic cells, expanding under genotoxic stress. Unlike with TP53 mutations, where mechanisms of progression are defined, pathways underlying clonal fitness and transformation in PPM1D mutant cells remain unclear. In collaboration with 5 academic institutions, we analyzed the clinical and molecular landscape of 337 patients with clonal hematopoiesis (CH) and clonal cytopenia of undetermined significance (CCUS) across four genotypes: PPM1Dmt/TP53wt (n= 170 [50%]), PPM1Dmt/TP53mt (n= 25 [7%]), TP53mt/PPM1Dwt (n=17 [5%]), and TP53wt/PPM1Dwt (n= 125 [38%]). All PPM1D variants were truncating, located in exon 6 of the gene, with a median variant allele frequency (VAF) of 6% (0.3-64%). The PPM1Dmt/TP53mt genotype was most frequently encountered in therapy related (t)CH/CCUS (80%, 66.5%, 76.5% and 19%; p= <0.001) and had a shorter time interval to detection from last genotoxic exposure (6.2, 5.9, 11.25, and 24.5 months; p= <0.001), in comparison to PPM1Dmt/TP53wt, TP53mt/PPM1Dwt and TP53wt/PPM1Dwt genotypes, respectively. Acknowledging the short follow-up duration, rates of malignant transformation were lower in PPM1Dmt/TP53wt (2%) and PPM1Dmt/TP53mt (4%) groups, in comparison to PPM1Dwt/TP53wt (12%) and PPM1Dwt/TP53mt (17%) groups (p= <0.001), respectively. In summary, PPM1D mutations are frequently observed in t-CH/CCUS, with low median VAFs and are associated with low rates of progression, even when co-mutated with TP53.
    DOI:  https://doi.org/10.1182/bloodadvances.2025018031
  2. Am J Hematol. 2026 Jan 09.
    Long-Term Outcomes of Stem Cell Transplant in Older Patients With Acute Myeloid Leukemia Treated With Venetoclax-Based Therapies.
    Keith W Pratz, Courtney D DiNardo, Martha Arellano, Michael J Thirman, Vinod Pullarkat, Pamela S Becker, B Douglas Smith, Meng Zhang, Kaylee Miu, Jalaja Potluri, Daniel A Pollyea.
      
    Keywords:  AML; VIALE‐A; stem cell transplant; venetoclax
    DOI:  https://doi.org/10.1002/ajh.70204
  3. Blood. 2026 Jan 05. pii: blood.2025030230. [Epub ahead of print]
    Bone marrow failure, somatic rescue by p53 inactivation, and enhanced leukemogenesis in germline ERCC6L2 disease.
    Roman Schimmer, Nancy Klemm, Jonas Fullin, Ebru Topcu, Milena Treacy, Karolina Zielinska, Cyril Doerdelmann, Daphne Devesa-Serrano, Melissa Lock, Francisco Caiado, Christian Koch, Nadjia Dietliker, Rahel Schwotzer, Marco Matteo Buehler, Mikko Myllymäki, Kari J Kurppa, Markus G Manz, Massimo Lopes, Steffen Boettcher.
      Recessively inherited loss-of-function mutations in Excision Repair Cross-Complementing 6 like 2 (ERCC6L2) cause a bone marrow failure (BMF) syndrome characterized by moderate cytopenias, frequent somatic TP53 mutations, and a propensity to develop myeloid malignancies. The pathophysiology and molecular mechanisms underlying the BMF syndrome as well as its association with TP53-mutant clonal hematopoiesis (CH) and myeloid malignancies have remained poorly understood. Using novel preclinical in vitro and in vivo model systems, we demonstrate that Ercc6l2 maintains the competitive fitness of hematopoietic stem and progenitor cells (HSPCs) by mitigating replication stress. Sustained replication stress and DNA damage in Ercc6l2-deficient HSPCs cause p53 pathway activation followed by cell cycle arrest and apoptosis. Moreover, Ercc6l2 deficiency results in decreased expression of master hematopoietic regulators Runx1 and Gata1 in HSPCs. Altogether, loss of Ercc6l2 leads to reduced HSPC numbers, bone marrow hypocellularity, and cytopenias. Notably, somatic Trp53 mutations restore cellular fitness of Ercc6l2-deficient HSPCs by abrogating p53 pathway activation and restoring Runx1 and Gata1 expression, thereby correcting the BMF phenotype. However, p53 loss fails to normalize replication stress, allowing for the accumulation of DNA damage over time which increases the likelihood for leukemic transformation. Our data uncover the pathogenesis of ERCC6L2 disease and provide a prototypic example of clonal compensation in BMF syndromes, where somatic mutations in leukemia-associated genes - in this case TP53 - transiently improve blood cell production at, however, the expense of increasing leukemogenic potential.
    DOI:  https://doi.org/10.1182/blood.2025030230
  4. Haematologica. 2026 Jan 08.
    Clinical outcomes of venetoclax combined with hypomethylating agents versus hypomethylating agents alone in TP53-mutated myelodysplastic syndromes.
    Mahmood Aldapt, Yu-Hung Wang, Kashish J Shah, Mobachir El Kettani, James Foran, Mohamed Kharfan-Dabaja, Hemant Murthy, Aref Al-Kali, Mithun V Shah, Hassan Alkhateeb, Antoine N Saliba, William Hogan, Cecilia Arana Yi, Lisa Sproat, Nathan Punwani, Nandita Khera, Jeanne Palmer, Mark Litzow, Ayalew Tefferi, Naseema Gangat, Mrinal M Patnaik, Talha Badar.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2025.289268
  5. bioRxiv. 2025 Dec 22. pii: 2025.10.16.682831. [Epub ahead of print]
    A Druggable Tumor Suppressor and Leukemic Stem Cell Marker.
    Yi Pan, Xiaduo Meng, Chen Wang, Wenxuan Zhou, Yibo Chen, Richard D Hammer, Hong Zheng, Gerhard Hildebrandt, Xunlei Kang.
      Acute myeloid leukemia (AML) often enters remission after chemotherapy but frequently relapses due to chemotherapy-resistant leukemic stem cells (LSCs). Relapsed AML remains largely unresponsive to current therapies and carries a poor prognosis. We developed a large-language model (LLM) agent that incorporates multi-modal data to nominate druggable therapeutic targets for AML. We identified that higher expression of AGTR2 (encoding AT2R) is associated with better chemotherapy response and longer survival. In functional studies of 68 primary human AML samples, we found that LSCs consistently lacked AT2R expression. Across both CD34-expressing and -non-expressing AML samples, AT2R expression positively correlated with CD34 and CD117 expression. In patient-derived xenograft (PDX) models using 21 primary AML samples, AT2R⁻ cells initiated leukemia, whereas AT2R⁺ cells failed to do so. AT2R⁻ cells gave rise to both AT2R⁺ and AT2R⁻ progeny, suggesting hierarchical differentiation. Following chemotherapy in AML PDX mice, bone marrow analysis showed a marked enrichment of AT2R⁻ cells and depletion of AT2R⁺ cells, indicating that AT2R⁻ cells drive minimal residual disease and relapse. These results support the role of AT2R absence as a marker of LSCs. We observed reduced AT2R expression in AML cells compared to healthy peripheral blood and bone marrow mononuclear cells, suggesting a tumor suppressor role. Whole-genome sequencing of AML patients revealed no functional mutations in AGTR2 . However, 3D chromatin and epigenetic analyses uncovered frequent chromatin rearrangements involving AGTR2 promoter-silencer interactions, indicating epigenetic silencing as a likely mechanism for AT2R downregulation in AML. To validate the tumor suppressor role of AT2R, we developed murine AML models driven by MLL-AF9 or AML1-ETO9a fusions with either Agtr2 knockdown or enforced expression. Agtr2 knockdown accelerated leukemogenesis, while enforced Agtr2 expression delayed AML progression. In these models, enforced Agtr2 expression reduced LSC frequency, impaired cell cycle progression, and decreased AML stemness, as confirmed by limiting dilution assays and analysis of LSC-enriched populations. Mechanistically, enforced Agtr2 expression suppressed fatty acid metabolism - a key driver of AML stemness and growth - and inhibited downstream signaling pathways, including GSK3, PI3K/AKT, and Wnt/β-catenin. This led to reduced SREBF1 activity, confirmed by protein level changes and CUT&Tag assays. We tested buloxibutid (C21), a small-molecule AT2R agonist currently in phase II trials for idiopathic pulmonary fibrosis, in AML PDX models derived from 20 de novo and 6 relapsed AML samples. C21 significantly inhibited AML progression and enhanced the efficacy of chemotherapy, particularly in relapsed AML models.
    DOI:  https://doi.org/10.1101/2025.10.16.682831
  6. Blood Neoplasia. 2026 Feb;3(1): 100181
    Impact of European LeukemiaNet-guided postremission therapy on outcomes of patients with AML from 2010 to 2022.
    Andrew F Berdel, Julian Ronnacker, Daniela V Wenge, Lina J Kolloch, Philipp Berning, Linus Angenendt, Tobias J Brix, Annette Westermann, Klaus Wethmar, Torsten Kessler, Andrea Kerkhoff, Rolf M Mesters, Christian Reicherts, Jan-Henrik Mikesch, Wolfgang E Berdel, Georg Lenz, Christoph Schliemann, Matthias Stelljes.
      The European LeukemiaNet (ELN) classification for acute myeloid leukemia (AML) incorporates cytogenetic and mutational risk profiles of AML to define separate risk groups that correlate with survival outcomes. Recommendations for postremission treatment (PRT) intensity, mainly allogeneic hematopoietic stem cell transplant, are based on these risk groups. In-depth genetically defined cohorts of registries or clinical trials, often reported as retrospective real-world validation cohorts, contain an inherent bias as patients were not treated according to recommendations matching time intervals of the respective ELN classification. We analyzed 662 patients with AML who received intensive induction therapy at our center between 2010 and 2022. Patients were classified according to ELN 2010 if treated between 2010 and 2016, and ELN 2017 if treated between 2017 and 2022. Overall survival (OS) and relapse-free survival (RFS) significantly improved for patients treated between 2017 and 2022 compared with those treated between 2010 and 2016 (4-year OS, 60% vs 40%; 4-year RFS, 54% vs 35%). To eliminate treatment bias, patients treated between 2017 and 2022 were retrospectively reclassified for genetic risk according to ELN 2010 and compared with regularly classified patients treated between 2010 and 2016. The improved outcome was particularly evident for intermediate-risk (IR) patients, whereas favorable and adverse subgroups showed no significant difference. This is, to our knowledge, the first analysis examining the impact of ELN-guided PRT in the context of treatment algorithms applied in the respective ELN time period. We conclude that the shift of risk groups between ELN 2010 and 2017, along with the resulting intensified PRT, contributed to significantly improved survival of patients with AML, particularly those with IR.
    DOI:  https://doi.org/10.1016/j.bneo.2025.100181
  7. Am J Hematol. 2026 Jan 08.
    Post-FDA Approval Experience With Momelotinib in JAK Inhibitor-Naïve Myelofibrosis: Focus on Anemia Response and Treatment-Emergent Nephropathy and Peripheral Neuropathy.
    Ayalew Tefferi, Maymona Abdelmagid, Jeanne M Palmer, Aref Al-Kali, Cecilia Y Arana Yi, Aasiya Matin, Hassan B Alkhateeb, Talha Badar, Yassin Bashir, Kaaren K Reichard, Rong He, Animesh Pardanani, Naseema Gangat.
      Real-world experience using momelotinib as first-line JAK2 inhibitor therapy in myelofibrosis. Anemia response was moderate (23%) while treatment-emergent adverse events included nephropathy (29%) and peripheral neuropathy (20%).
    Keywords:  SH2B3; fedratinib; pacritinib; ruxolitinib; side effects
    DOI:  https://doi.org/10.1002/ajh.70203
  8. Blood. 2026 Jan 05. pii: blood.2025030722. [Epub ahead of print]
    Phase 3 study of intensive chemotherapy with or without dasatinib in core-binding factor acute myeloid leukemia.
    Hartmut Döhner, Daniela Späth, Maral Saadati, Walter Fiedler, Katharina S Götze, Elisabeth Koller, Jörg Westermann, Wichard Vogel, Michael Heuser, Michael Lübbert, Hans-Joachim Tischler, Ulrich Germing, Lino Lars Teichmann, Lars Fransecky, Albert Wölfler, David Nachbaur, Bernd Hertenstein, Roland Schroers, Uwe M Martens, Stephanie von Harsdorf, Markus P Radsak, Gregor Aschauer, Stefanie Weißhaar, Andrea Corbacioglu, Anika Schrade, Verena I Gaidzik, Felicitas R Thol, Peter Paschka, Lars Bullinger, Axel Benner, Konstanze Döhner, Arnold Ganser.
       BACKGROUND: Core-binding factor acute myeloid leukemia (CBF-AML) is associated with KIT mutations and deregulated expression of KIT.
    AIMS: We report results from the randomized, open-label, phase 3 trial of intensive chemotherapy with or without the multi-kinase inhibitor dasatinib in adult patients with CBF-AML.
    METHODS: Patients received "3+7" induction therapy, followed by 4 cycles of high-dose cytarabine; in the investigational arm, patients received dasatinib 100 mg QD on days 8-21 in induction, and on days 6-28 in consolidation cycles, followed by 12-month single-agent dasatinib 100 mg QD. Primary endpoint was event-free survival (EFS). Secondary endpoints included overall survival, relapse-free survival, and cumulative incidence of relapse.
    RESULTS: 202 patients were randomly assigned to the standard arm (n=102) and to the dasatinib arm (n=100). Median age was 49 years (range, 18, 77); 94 patients had t(8;21), 108 had inv(16)/t(16;16); 58 (28.7%) patients had a KIT co-mutation. There was no statistically significant difference in EFS (HR 0.92, 95%-CI 0.63, 1.33; p=0.66) or secondary endpoints between treatment arms. There was also no significant difference in EFS in subgroup analyses according to age, CBF-AML type, and KIT mutation status. The incidence of serious adverse events was higher in the investigational arm (64%) than in the standard arm (36%).
    CONCLUSION: In patients with CBF-AML, the addition of dasatinib to intensive chemotherapy failed to improve survival outcomes. The addition of dasatinib was associated with an increase in toxicity. This trial was registered at www.
    CLINICALTRIALS: gov as NCT02013648.
    DOI:  https://doi.org/10.1182/blood.2025030722
  9. Blood Cancer J. 2026 Jan 05. 16(1): 1
    Triple-negative primary myelofibrosis: a comparative analysis of phenotype, genotype, and outcome.
    Yassin A Bashir, Ahmed A Abdelrheem, Maymona Abdelmagid, Kaaren K Reichard, Rong He, Cinthya J Zepeda Mendoza, Animesh Pardanani, Naseema Gangat, Ayalew Tefferi.
      
    DOI:  https://doi.org/10.1038/s41408-025-01440-4
  10. Cell Rep Med. 2026 Jan 08. pii: S2666-3791(25)00613-5. [Epub ahead of print] 102540
    ΔNp73 isoform defines a TP53-mutant-like poor-risk subgroup of acute myeloid leukemia.
    Diego A Pereira-Martins, Cesar Ortiz, Isabel Weinhäuser, Albertus T J Wierenga, Vincent van den Boom, Fatemeh Mojallali, Dominique Sternadt, Nisha K van der Meer, Shanna M Hogeling, Thiago M Bianco, Prodromos Chatzikyriakou, Douglas R Silveira, Emanuele Ammatuna, Antonio R Lucena-Araujo, Lynn Quek, Gerwin Huls, Eduardo M Rego, Jan Jacob Schuringa.
      Among acute myeloid leukemia (AML) patients, a subgroup remains notoriously refractory to current treatment options, with underlying mechanisms poorly understood. Here, using a multi-omics approach, we reveal that this resistant patient subgroup is characterized by high expression of the oncogenic TP73 isoform ΔNp73, exhibiting similarly poor outcomes as TP53-mutant AML. ΔNp73, which lacks a transcriptional activation domain but retains chromatin-binding properties, competes with TP53 for specific gene targets, thereby downregulating TP53 signaling. We demonstrate that the transcription factor CEBPA controls ΔNp73 expression in AML cells by binding to an intragenic enhancer region. Genetic or pharmacological inhibition of the transcriptional activity of CEBPA with guanfacine reduces ΔNp73 levels and restores drug sensitivity involving ferroptosis-mediated cell death, acting synergistically with venetoclax. Our study sheds light on a previously undercharacterized poor-risk subgroup of AML, which may support patient stratification and inform treatment considerations.
    Keywords:  AML PDX models; CEBPA; SREBP/SREBF; TP53-mutated AML; TP73; acute myeloid leukemia; drug resistance; ferroptosis; guanfacine; poor prognosis prediction
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102540
  11. Blood. 2026 Jan 05. pii: blood.2025030489. [Epub ahead of print]
    Clonal Hematopoiesis and Lymphoma-Associated Mutations in Hematopoietic Progenitors in B-Cell Non-Hodgkin Lymphoma.
    Laura Wiegand, Patricia Silva, Daniel Noerenberg, Friederike Christen, Klara Kopp, Benjamin Nick Locher, Pelle Löwe, Marlon Tilgner, Robert Altwasser, Vanessa Storzer, Catarina M Stein, Franziska Briest, Christopher Maximilian Arends, Mareike Frick, Jana Ihlow, Anna Dolnik, Naveed Ishaque, Ulrich Keller, Il-Kang Na, Livius Penter, Lars Bullinger, Raphael Hablesreiter, Frederik Damm.
      Gene-specific expansion patterns were evident among the most frequent CH lesions, with DNMT3A-mutant clones exhibiting impaired hematopoietic differentiation and TET2-mutant clones showing multi-lineage propagation. Notably, identical CH clones were detected in 41% of corresponding lymphomas, displaying distinct clonal dynamics: tumor-promoting CH (expansion in B-NHL; 10/16 clones; mainly TP53) and tumor-infiltrating CH (no expansion; mainly DNMT3A). Moreover, we identified lymphoma-associated mutations in flow-sorted hematopoietic progenitors from patients with indolent but not aggressive B-NHL and observed a stepwise accumulation of mutations along the lymphoid differentiation path. Single-cell genotyping confirmed the presence of mutated progenitors in 3 follicular, 2 mantle cell and 2 marginal zone lymphoma patients, providing direct evidence of a pre-neoplastic state in disease pathogenesis. Our findings offer novel insight into the cellular origin of nodal B-NHLs and highlight a previously underappreciated role for early clonal events involving the stem/progenitor cell compartment.
    DOI:  https://doi.org/10.1182/blood.2025030489
  12. Curr Opin Hematol. 2025 Dec 30.
    Navigating prognostic stratification and approach to TP53-mutated myeloid neoplasms.
    Talha Badar, Ayalew Tefferi, Naseema Gangat.
       PURPOSE OF REVIEW: TP53-mutated (TP53-MT) myeloid neoplasms (MN) represent one of the most challenging disease subsets due to their distinct pathobiology, frequent association with therapy-related disease, chemo-resistant phenotype, and dismal outcomes. The prognostic impact of TP53-MT is not uniform and is influenced by disease state, allelic burden, and co-occurring cytogenetic and molecular aberrations that shape disease trajectory. While current prognostic models incorporate TP53 status, they incompletely capture the heterogeneity within TP53-MT MN. Therapeutic options remain limited, with allogeneic stem cell transplantation being the only intervention offering long-term survival in selected patients.
    RECENT FINDINGS: Novel approaches, including p53 reactivators and anti-CD47 antibodies in combination with standard-of-care therapies, have been explored; however, none has yet transformed the natural history of TP53-MT MN.
    SUMMARY: This review highlights the current understanding of TP53-MT MN, evolving strategies of prognostic stratification and propose a practical framework for clinical management. We further discuss the critical unmet need for collaborative, biologically informed clinical trials to improve outcomes of this challenging disease entity.
    Keywords:  ; acute myeloid leukemia; allogeneic hematopoietic stem cell transplantation; myelodysplastic syndrome; myeloproliferative neoplasm
    DOI:  https://doi.org/10.1097/MOH.0000000000000906
  13. Am J Hematol. 2026 Jan 07.
    Hematologic Landscape of Adult Patients With Diamond-Blackfan Anemia Syndrome.
    Nicolas Lecornec, Flore Sicre de Fontbrune, Edouard Forcade, Loïc Garçon, Louis Terriou, Pierre Cougoul, Karen Delavigne, Isabelle Marie, Isabelle Brindel, Éric Deconinck, Étienne Daguindau, Shanti Amé, Marie-Pierre Ledoux, Laurence Sanhes, Stanislas Nimubona, Guy Leverger, Marianne de Montalembert, Régis Peffault de Latour, Jean-Hugues Dalle, Pierre Fenaux, Lydie Da Costa, Thierry Leblanc.
      Information about Diamond-Blackfan anemia syndrome (DBAS), a ribosomopathy associated with anemia, congenital anomalies and cancer predisposition is limited in adults. Using the French DBAS registry, 235 adult patients with DBAS were analyzed for hematological outcomes. At last follow-up, anemia, neutropenia, thrombocytopenia, and pancytopenia affected respectively 78%, 31%, 15%, and 11% of the patients. There was no severe aplastic anemia outside of clonal evolution. Among patients without DBAS-specific treatment (e.g., steroids or red blood cell transfusions), the incidence of anemia, neutropenia, and thrombocytopenia was 52%, 35%, and 10%, highlighting that treatment independence does not mean hematologic remission. Four patients developed myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), all associated with poor-risk features and dismal outcomes. Observed to expected ratios were 155 for MDS and 55.4 for AML, confirming a major risk-excess despite stringent criteria for MDS diagnosis. With a median follow-up of 32.2 years (IQR 26-44), overall survival (OS) was 98.0% (95% CI, 95.8-100), 90.6% (95% CI, 84.2-97.5), and 70.7% (95% CI, 57.3-87.2) at 30, 40, and 50 years respectively. Solid and hematologic cancers were the main cause of death. This study demonstrates, in a large cohort of adults with DBAS, that cytopenias beyond anemia are frequent and persistent. Myeloid neoplasms occur with a high incidence and dismal outcomes. These findings highlight the need for risk stratification, tailored surveillance, and optimized therapeutic strategies in this vulnerable population.
    DOI:  https://doi.org/10.1002/ajh.70197
  14. bioRxiv. 2025 Dec 26. pii: 2025.12.24.696284. [Epub ahead of print]
    CK2 inhibitor, CX-4945, enhances BH3 priming and promotes apoptosis of venetoclax-resistant AML by targeting antiapoptotic proteins.
    Muhammad Daniyal, Rajesh Rajaiah, Upendarrao Golla, Marudhu Pandiyan Shanmugam, Koby Duke, Katherine Mercer, Yasin Uzun, Hannah Valensi, Jeremy Hengst, Sinisa Dovat, Yi Qiu, Suming Huang, Chandrika G Behura.
      Acute myeloid leukemia (AML), the most common hematologic malignancy, generally has a poor prognosis. Despite initial favorable responses to the BCL2 inhibitor venetoclax (VEN), remission is transient, and AML is eventually fatal. Resistance to VEN is primarily due to the overexpression of anti-apoptotic proteins, including MCL-1, BCL2L1 (BCL-XL), and BCL2A1. Casein kinase II (CK2) is a serine-threonine kinase and a known suppressor of apoptosis. We and others have reported that protein kinase CK2 activity is high in leukemic stem cells (LSCs) and associated with resistance to chemotherapy. We have shown that the selective CK2 inhibitor, CX-4945, suppresses BCL-XL and has a significant anti-tumor effect in AML preclinical models. CK2 expression and activity are high in venetoclax-resistant AML (VR-AML) cell lines. Genetic and pharmacological inhibition of CK2 significantly altered VR-AML gene signature, decreased MCL-1 protein level, increased BH3 priming and sensitized VR-AML cells to apoptosis. More importantly, CX-4945 selectively targeted LSCs (CD34+CD38-) and chemoresistant (CD123+CD47+) subpopulation in VR-AML. CX-4945 combined with VEN decreased leukemia burden and prolonged the survival of VR-AML cell line-derived and patient-derived xenografts compared to either drug alone. The combinatorial treatment was well tolerated in mice without additional myelosuppression or organ toxicity. CX-4945 (silmitasertib) is being tested in several early-phase clinical trials against adult and pediatric cancers. These preclinical results support the use of CX-4945 in combination with VEN to overcome resistance to apoptosis and re-sensitize VR-AML to chemotherapy.
    DOI:  https://doi.org/10.64898/2025.12.24.696284
  15. Am J Hematol. 2026 Jan 05.
    Randomized Comparison of Cardiotoxicity With 60 Versus 90 mg Daunorubicin in AML Induction Therapy.
    Stefan Markus Dendorfer, Katharina Schmidt-Brücken, Michael Kramer, Björn Steffen, Christoph Schliemann, Jan-Henrik Mikesch, Nael Alakel, Regina Herbst, Mathias Hänel, Maher Hanoun, Martin Kaufmann, Barbora Weinbergerova, Kerstin Schäfer-Eckart, Tim Sauer, Andreas Neubauer, Andreas Burchert, Claudia D Baldus, Jolana Mertová, Edgar Jost, Dirk Niemann, Jan Novák, Stefan W Krause, Sebastian Scholl, Andreas Hochhaus, Gerhard Held, Tomáš Szotkowski, Andreas Rank, Christoph Schmid, Lars Fransecky, Sabine Kayser, Markus Schaich, Frank Fiebig, Annett Haake, Johannes Schetelig, Jan Moritz Middeke, Friedrich Stölzel, Uwe Platzbecker, Christian Thiede, Carsten Müller-Tidow, Wolfgang E Berdel, Gerhard Ehninger, Jiri Mayer, Hubert Serve, Martin Bornhäuser, Christoph Röllig.
      Anthracyclines are an essential component of induction therapy for acute myeloid leukemia (AML), but their optimal dosing and the associated risk for cardiotoxicity remain under debate. The DaunoDouble trial compared daunorubicin at 60 (Dauno60) versus 90 mg/m2 (Dauno90) in combination with cytarabine (100 mg/m2 for 7 days) in newly diagnosed AML patients aged 18-65 years. Cardiac function was assessed by left ventricular ejection fraction (LVEF) and cardiac biomarkers (high-sensitivity troponin T [hsTnT], NT-proBNP) before treatment and on Day 15 in 317 randomized patients. Median LVEF declined significantly from 65% [IQR 60%-68.5%] to 61% [IQR 58%-67.8%] across all patients (p < 0.01), without significant differences between treatment arms. NT-proBNP levels measured after induction therapy correlated negatively with LVEF at the same time point (ρ = -0.24, p = 0.02), but did not change significantly during induction-neither between Day 1 and 15 nor between treatment arms. HsTnT levels increased significantly from 5 [IQR 4-8] to 8 ng/L [IQR 6-14] across all patients (p < 0.01), with higher post-induction values in the Dauno90 group (9.5 ng/L [IQR 7-14]) compared to Dauno60 (7 ng/L [IQR 5-14]; p < 0.01). In exploratory subgroup analyses, post-induction hsTnT levels were also significantly higher in patients with obesity and arterial hypertension. These findings provide evidence of a dose-dependent cardiotoxic effect of daunorubicin, already apparent at standard induction doses, and underscore the importance of early cardiac monitoring. Long-term follow-up will be essential to determine the clinical significance of these early changes. Trial Registration: ClinicalTrials.gov identifier: NCT02140242.
    Keywords:  acute myeloid leukemia; anthracycline chemotherapy; cardiotoxicity; daunorubicin dosing; high‐sensitivity troponin T
    DOI:  https://doi.org/10.1002/ajh.70160
  16. Blood Neoplasia. 2026 Feb;3(1): 100171
    Safety of gemtuzumab ozogamicin with cytarabine, daunorubicin, and midostaurin induction in FLT3-mutated AML.
    Jayanshu Jain, Kelly Pugh, Shivani Handa, Kaitlyn M Dvorak-Kornaus, Qiuhong Zhao, Roland B Walter, Rachel Cook, Jennifer Saultz, Ronan Swords, Junyang Li, George S Laszlo, Nicole R Grieselhuber, Alice S Mims, Karilyn T M Larkin, Kieran Sahasrabudhe, James S Blachly, Gregory K Behbehani, Ann-Kathrin Eisfeld, Meixiao Long, Andrew Srisuwananukorn, Kristin L Koenig, Uma Borate.
      This phase 1 study investigated the addition of gemtuzumab ozogamicin (GO) to intensive chemotherapy with cytarabine, daunorubicin, and midostaurin in 21 patients with newly diagnosed (ND) FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML). Four dose levels of GO were evaluated. The use of GO was tolerable, with all dose-limiting toxicities similar to those seen in standard-of-care treatment. After induction, the median time to platelet recovery was 26 days, and the median time to absolute neutrophil count (ANC) recovery was 27 days. The maximum tolerated dose was cytarabine 100 mg/m2 on days 1 to 7, midostaurin 50 mg twice daily on days 8 to 21, daunorubicin 60 mg/m2 on days 1 to 3, and GO 3 mg/m2 on days 1 and 4. For the 18 patients who were evaluable for response after induction therapy, 16 patients (76%) achieved a composite complete response (complete remission [CR] + CR with incomplete hematologic recovery), and 2 (10%) had stable disease. Of the 14 patients who proceeded to consolidation, 5 discontinued the study for transplant, 1 for disease progression, and 1 for physician discretion. Seven patients completed consolidation therapy, all of whom achieved a CR. In total, 13 of the 21 patients (62%) received a hematopoietic stem cell transplant. Our results show that GO can safely be combined with intensive chemotherapy with midostaurin in ND, FLT3-mutated AML. This trial was registered at www.clinicaltrials.gov as #NCT03900949.
    DOI:  https://doi.org/10.1016/j.bneo.2025.100171
  17. bioRxiv. 2025 Dec 22. pii: 2025.12.19.695528. [Epub ahead of print]
    The Nicotinamide Salvage Pathway is a Metabolic Vulnerability of High-Risk MDS Stem Cells.
    CUIJBP consortium
      High-risk myelodysplastic syndrome (HR-MDS) is a malignant clonal disorder originating in hematopoietic stem and progenitor cells (HSPCs). The current standard of care for HR-MDS patients is hypomethylating agents; however, the response rate is poor. There is thus a need to explore vulnerabilities of HR-MDS HSPCs for better clinical outcomes. We demonstrate that HR-MDS HSPCs have significant upregulation of metabolic proteins required for glycolysis, citric acid cycle, and oxidative phosphorylation. Consistently, we see increased oxygen consumption rate in HR-MDS HSPCs compared to healthy, suggesting an increased metabolic rate. Corroboratively, compared to healthy HSPCs, HR-MDS HSPCs have increased abundance of mitochondrial complex I proteins, which are NADH dehydrogenases, and crucial for energy production. Therefore, we investigated whether HR-MDS HSPCs are functionally reliant on NAMPT, the rate-limiting enzyme in the nicotinamide salvage pathway of NAD anabolism. NAMPT inhibition significantly decreased NAD(H) in HR-MDS HSPCs. Consequently, NAMPT inhibition reduced the oxygen-consuming capacity of HR-MDS-HSPCs compared to healthy. Importantly, NAMPT inhibition significantly impaired the self-renewal and colony-forming potential, increased cell death and reduced disease burden specifically of HR-MDS HSPCs, compared to healthy controls. Collectively, our data suggest that NAMPT is selectively required for the function and survival of HR-MDS HSPCs representing a promising therapeutic target.
    DOI:  https://doi.org/10.64898/2025.12.19.695528
  18. Leukemia. 2026 Jan 08.
    Identifying targeted therapies for CBFA2T3::GLIS2 acute myeloid leukemia.
    Fanny Gonzales, Constanze Schneider, Gabriela Alexe, Shan Lin, Delan Khalid, Montserrat Alvarez, Allen Basanthakumar, Jana M Ellegast, Lucy Merickel, Silvi Salhotra, Audrey Taillon, Mariateresa Giaimo, Mark Wunderlich, Marc Ansari, Jennifer A Perry, Barbara Degar, Yana Pikman, Kimberly Stegmaier.
      CBFA2T3::GLIS2-positive pediatric acute myeloid leukemia (AML) remains one of the worst prognostic AML subgroups. To uncover innovative targeted therapy approaches in this disease subtype we performed genome-scale CRISPR-Cas9 screening that highlighted a strong, selective dependency on JAK2 compared to other types of cancer. Using a doxycycline-inducible JAK2 knockout (KO) system, we validated JAK2 dependency in CBFA2T3::GLIS2 cell lines, observing impaired proliferation in vitro and in vivo and apoptosis induction in vitro. Both type I (ruxolitinib) and type II (CHZ868) JAK2 inhibitors showed selective in vitro activity in CBFA2T3::GLIS2-positive AML models. To identify resistance and sensitizer mechanisms to JAK2 inhibitors, we used CRISPR-Cas9 ruxolitinib anchor screening in CBFA2T3::GLIS2 AML. sgRNAs targeting negative regulators of the MAPK pathway were enriched in the ruxolitinib-treated cells. Similarly, CBFA2T3::GLIS2 AML sublines grown to resistance under chronic ruxolitinib treatment expressed pathogenic NRAS mutations. Both approaches converged on MAPK pathway activation as a resistance mechanism to ruxolitinib treatment. Combining ruxolitinib with MEK inhibitors showed a synergistic effect in cell lines and patient-derived xenograft (PDX) cells expressing the fusion and in vivo activity in a CBFA2T3::GLIS2 AML PDX, suggesting a potential approach to target this signaling circuitry in this poor outcome AML subtype.
    DOI:  https://doi.org/10.1038/s41375-025-02845-7
  19. Blood Adv. 2026 Jan 07. pii: bloodadvances.2025018724. [Epub ahead of print]
    Impact of Statin Use on Cardiovascular and Hematologic Outcomes Among Patients with Myeloproliferative Neoplasms.
    Orly Leiva, Steven Soo, Olivia C Liu, Victor You, Andrew Stephen Palmer, Justin Abraham Kahla, Yasmeen Murtaza, Olatoyosi Odenike, Anand A Patel, Jeanne DeCara, Patrycja M Dubielecka, Max Petersen, Michelle H Lee, Joan How, Gabriela S Hobbs.
      Myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), are chronic myeloid neoplasms associated with increased risk of cardiovascular disease (CVD). Statins are a common group of cholesterol-lower medications recommended for the primary and secondary prevention of CVD, including arterial thrombotic events. Emerging evidence suggests that statins may reduce the risk of developing MPNs and their use may be associated with improved survival. However, statins impact on cardiovascular and hematologic outcomes among patients with MPNs remains uncharacterized. We conducted a multicenter retrospective cohort study of patients with MPNs who had at least one transthoracic echocardiogram (TTE) from 2010 to 2024. Inverse-probability treatment weighting (IPTW) competing-risk regression analysis was performed to assess the association between statin use at time of index TTE on major adverse cardiovascular events (MACE), MPN disease progression, and all-cause death. MPN patients were analyzed as a whole and separately by type (ET or PV and MF). A total of 669 patients were included, 43.9% were on statin use, 50.5% were female, 83.9% were White, 78.8% had JAK2 driver mutation, and 72.9% had class I guideline indication for statin therapy. There were 267 (39.9%) PV, 234 (35.0%) ET, and 168 (25.1%) MF patients. After IPTW, statin use was associated with lower risk of MACE (SHR 0.83, 95% CI 0.70 - 0.98) but not MPN disease progression (SHR 0.96, 95% CI 0.72 - 1.29) or all-cause death (HR 1.04, 95% CI 0.87 - 1.24). Among patients with ET or PV, statin use was associated with lower risk of MACE (SHR 0.78, 95% CI 0.64 - 0.95) but not MPN progression (SHR 1.03, 95% CI 0.74 - 1.44) or all-cause death (HR 0.85, 95% CI 0.68 - 1.06). Among patients with MF, there was no difference in MACE, leukemia progression, or all-cause death. Among patients with MPNs who underwent TTE, statin use was associated with lower risk of MACE, particularly among patients with ET or PV. However, there was no association between statin use and all-cause death or MPN disease progression. Statin therapy is underutilized in this patient population. Further studies are needed to explore the utility of statin therapy in patients with MPN and identify patients who would benefit most from statin therapy.
    DOI:  https://doi.org/10.1182/bloodadvances.2025018724
  20. Sci Adv. 2026 Jan 09. 12(2): eady0301
    Nat10-mediated ac4C epitranscriptomics orchestrates hematopoietic stem/progenitor cell fate determination via translation control.
    Feng Huang, Yushuai Wang, Weiwei Gao, Xiuxin Zhang, Jiajia Zhou, Ying Yang, Hongjie Mo, Minhan Wang, Qi Chen, Guangdun Peng, Jianjun Chen, Huilin Huang, Hengyou Weng.
      Epigenetic regulation is crucial for balancing hematopoietic stem cell (HSC) self-renewal and differentiation, thereby maintaining hematopoietic homeostasis. Although Nat10-mediated RNA ac4C modification has been implicated in malignant hematopoiesis, its role in normal hematopoiesis remains unexplored. Here, we developed ULAC-seq to map ac4C in rare hematopoietic stem/progenitor cells (HSPCs) and revealed dynamic, cell-type-specific ac4C patterns, peaking in megakaryocyte-erythroid progenitors (MEPs), correlating with elevated Nat10 expression. Nat10 knockout disrupts HSC self-renewal and arrests MEP differentiation, leading to fetal and postnatal hematopoietic failure. Mechanistically, Nat10 deposits ac4C on mRNAs encoding key hematopoietic transcription regulators (e.g., Nfix), thereby enhancing their translation. Nat10 loss reduces Nfix protein levels and suppresses expression of its target genes (e.g., Mpl) that govern HSPC fate, while Nfix reconstitution rescues colony-forming defects in Nat10-null HSPCs. Our findings reveal that Nat10 orchestrates hematopoiesis through ac4C-dependent translational control of transcriptional factors, establishing an epitranscriptome-transcriptome regulatory axis essential for HSC maintenance and function.
    DOI:  https://doi.org/10.1126/sciadv.ady0301
  21. Am J Hematol. 2026 Jan 05.
    Analysis of Patients With Monocytic and Monocytic-Like Acute Myeloid Leukemia, Including AML-M4 and AML-M5, Treated With Venetoclax Plus Azacitidine.
    Marina Konopleva, Courtney D DiNardo, Yan Sun, Paul Jung, Sanam Loghavi, Jalaja Potluri, Monique Dail, Brenda Chyla, Daniel A Pollyea.
      
    DOI:  https://doi.org/10.1002/ajh.70161
  22. Am J Hematol. 2026 Jan 08.
    Clonal Hematopoiesis of Indeterminate Potential and Clonal Cytopenias of Undetermined Significance: 2026 Update on Clinical Associations and Management Recommendations.
    Abhishek A Mangaonkar, Kelly L Bolton, Mrinal M Patnaik.
       CONDITION OVERVIEW: Clonal hematopoiesis (CH) refers to the presence of somatic variants in hematopoietic stem and progenitor cells (HSPC) that result in expansion over time.
    DIAGNOSIS: CH of indeterminate potential (CHIP) is operationally defined as pathogenic variants in oncogenic driver genes occurring in HSPCs at variant allele frequencies ≥ 2%.
    CLINICAL ASSOCIATIONS: CH is associated with increased risk for progressive cytopenias (also called clonal cytopenia of undetermined significance), hematological (predominantly myeloid but also lymphoid) neoplasms, cytosis (including monocytosis), and nonhematological conditions such as atherosclerotic cardiovascular and cerebrovascular disease. CH is linked to numerous other diseases including venous thromboembolism, type 2 diabetes mellitus, chronic obstructive pulmonary disease, osteoporosis, and gout, with a potential protective impact in Alzheimer's disease (AD).
    MANAGEMENT RECOMMENDATIONS: CH detection is becoming increasingly common due to the ubiquitous use of somatic and germline sequencing in clinical practice, particularly, in oncology. The clinical implications of CH are most relevant in therapy-related myeloid neoplasms (t-MN), with antecedent CH clones in genes such as TP53, PPM1D, and/or CHEK2 having a clear selection advantage. Furthermore, genetic predisposition to CH has provided some clarity on the origin and evolution of CH. We are currently defining the role for CH assessment in individuals with persistent (≥ 4 months) unexplained cytopenias, in patients with malignancies prior to adjuvant cytotoxic chemotherapy and/or radiation or radionuclide therapy, screening prior to autologous hematopoietic stem cell transplantation or chimeric antigen receptor T cell (CAR-T) therapy, and to work-up potentially germline mosaic variants.
    DOI:  https://doi.org/10.1002/ajh.70205
  23. Nat Rev Mol Cell Biol. 2026 Jan 06.
    Inflammageing and clonal haematopoiesis interplay and their impact on human disease.
    George Hajishengallis, Triantafyllos Chavakis.
      Clonal haematopoiesis of indeterminate potential (CHIP) is an ageing-related condition associated with a substantial fraction of circulating leukocytes having descended from a single somatically mutated haematopoietic stem cell (HSC). CHIP increases the risk of haematological malignancies and several chronic diseases (for example, cardiovascular pathologies) and contributes to persistent, low-grade inflammation or inflammageing. Inflammageing, in turn, promotes functional impairment of normal HSCs, including reduced self-renewal potential. By contrast, CHIP-mutant HSCs not only are resistant to inflammageing-induced functional decline but also gain a selective expansion advantage in an inflammatory environment. A recent surge of discoveries has increased our understanding of the CHIP-inflammageing interplay, from a mechanistic and clinical perspective, highlighting its broader relevance to age-related diseases. In this Review, we discuss the molecular and cellular mechanisms that cause CHIP, its interplay with inflammageing, as well as the pathophysiological consequences and the translational implications for diseases that affect older individuals.
    DOI:  https://doi.org/10.1038/s41580-025-00936-y
  24. Cell Chem Biol. 2026 Jan 06. pii: S2451-9456(25)00395-2. [Epub ahead of print]
    Scaffolding-dependent CASP1 constrains excessive cell-intrinsic inflammatory signaling in leukemia.
    Emma E Uible, Issac Choi, Courtnee A Clough, Aishlin Hassan, Annabelle J Anandappa, Julianna Fisher, Bibek Karki, Kathleen Hueneman, Kwangmin Choi, Eric J Vick, William Seibel, Kenneth D Greis, Lynn Lee, Courtney Jones, Timothy M Chlon, Jorge Henao-Mejia, Chandrashekhar Pasare, John T Cunningham, Andrew G Volk, Daniel T Starczynowski.
      Caspase-1 (CASP1) is best known for regulating IL-1β processing and pyroptosis; however, its role in leukemia has not been clearly defined. Here, we show that loss of CASP1 impairs leukemic cell growth, drives differentiation, and reduces leukemic burden in vivo, independent of its CASP1 protease activity. Instead, CASP1 functions as a scaffolding hub, controlling nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling via its interaction with raptor (RPTOR), a component of mTORC1. Deletion of CASP1 or disruption of its CARD domain induces excessive NF-κB activity and impairs leukemic cell function. We further developed a proteolysis-targeting chimera (PROTAC) degrader that selectively depletes Pro-CASP1 and suppresses leukemic cells. These findings reveal CASP1 as a regulator of mTORC1-NF-κB signaling in leukemia and highlight its scaffolding activity as a therapeutic vulnerability.
    Keywords:  AML; CASP1; NF-κB; RAPTOR; inflammasome; mTOR
    DOI:  https://doi.org/10.1016/j.chembiol.2025.12.002
  25. Blood. 2026 Jan 09. pii: blood.2025031080. [Epub ahead of print]
    Gastrin for the treatment of acute graft-versus-host disease of the stomach.
    Jana Gawron, Marie Czech, Tamina Rückert, Verena Holzmüller, Grigor Andreev, Ann-Cathrin Burk, Alina Hartmann, Sangya Chatterjee, Geoffroy Andrieux, Franziska Elisabeth Marquard, Anna-Sophia Baur, Anna-Verena Stell, Máté Krausz, Lukas M Braun, Natascha Osswald, Wolfgang Melchinger, Tobias Wertheimer, Andrea Isabel Proano-Vasco, Kristina Maas-Bauer, Annette Schmitt-Graeff, Melanie Boerries, Natalie Köhler, Francis Ayuketang Ayuk, Christoph Schell, Michael Quante, Robert Zeiser.
      Acute graft-versus-host disease (aGVHD) is a major cause of death after allogeneic hematopoietic cell transplantation (allo-HCT) and patients with steroid-refractory aGVHD have a dismal prognosis. We have previously shown that the enteroendocrine hormone glucagon-like peptide-2 (GLP-2) has tissue regenerative activity in the lower GI in mice and patients with steroid-refractory aGVHD. Here we explored the tissue protective effect of the enteroendocrine hormone gastrin for aGVHD of the stomach. We observed that aGVHD caused a loss of gastrin-producing G-cells and parietal cells (PCs) and an increase of pH in the stomach, while allogeneic T cells infiltrated the stomach wall. Pentagastrin treatment of aGVHD mice rescued the loss of PCs, normalized the pH in the stomach, increased stomach stem cell marker expression and abundance of LGR5+ cells, and changes in the stomach microbiome. Gastrin also increased the viability of stomach and small intestine organoids in vitro. Gast-/- mice experienced more severe aGVHD in the intestine and liver compared to WT mice, which was rescued by pentagastrin-treatment. In patients developing aGVHD, low gastrin levels in stomach biopsies were connected to reduced survival. Moreover, gastrin expression in the stomach correlated with aGVHD severity and tissue damage scores in independent patient cohorts. This study delineates the protective role of gastrin in aGVHD of the stomach in mice and patients and provides a rationale for therapeutic use of pentagastrin in a clinical trial for patients with aGVHD.
    DOI:  https://doi.org/10.1182/blood.2025031080
  26. Elife. 2026 Jan 07. pii: RP93645. [Epub ahead of print]13
    Identification of a Musashi2 translocation as a novel oncogene in myeloid leukemia.
    Kyle Spinler, Michael Hamilton, Jeevisha Bajaj, Yutaka Shima, Emily Diaz, Marcie Kritzik, Tannishtha Reya.
      Myeloid leukemias, diseases marked by aggressiveness and poor outcomes, are frequently triggered by oncogenic translocations. In the case of chronic myelogenous leukemia (CML), the BCR-ABL fusion initiates chronic phase disease with second hits allowing progression to blast crisis. Although Gleevec has been transformative for CML, blast crisis CML remains relatively drug resistant. Here, we show that MSI2-HOXA9, a translocation with an unknown role in cancer, can serve as a second hit in driving bcCML. Compared to BCR-ABL, BCR-ABL/MSI2-HOXA9 led to a more aggressive disease in vivo with decreased latency, increased lethality, and a differentiation blockade that is a hallmark of blast crisis. Domain mapping revealed that the MSI2 RNA binding domain RRM1 had a preferential impact on growth and lethality of bcCML relative to RRM2 or the HOXA9 domain. Mechanistically, MSI2-HOXA9 triggered global downstream changes with a preferential upregulation of mitochondrial components. Consistent with this, BCR-ABL/MSI2-HOXA9 cells exhibited a significant increase in mitochondrial respiration. These data suggest that MSI2-HOXA9 acts, at least in part, by increasing expression of the mitochondrial polymerase POLRMT and augmenting mitochondrial function and basal respiration in blast crisis. Collectively, our findings demonstrate for the first time that translocations involving the stem and developmental signal MSI2 can be oncogenic and suggest that MSI, which we found to be a frequent partner for an array of translocations, could also be a driver mutation across solid cancers.
    Keywords:  MSI2-HOXA9 translocation; Musashi2; bcCML; cancer biology; mouse; myeloid leukemia; oncogene
    DOI:  https://doi.org/10.7554/eLife.93645
  27. Leukemia. 2026 Jan 07.
    NUP98 rearrangements in adult AML patients: evaluation of clinical implications and identification of novel fusion partners.
    Kazuhisa Chonabayashi, Makoto Iwasaki, Junya Kanda, Hiroyuki Takamori, Akinori Yoda, Takahito Kawata, Shumpei Mizuta, Maki Sakurada, Tadakazu Kondo, Nobuhiro Hiramoto, Yasunori Ueda, Akihiko Gotoh, Mitsumasa Watanabe, Senji Kasahara, Yuichi Ishikawa, Hitoshi Kiyoi, Kazunori Imada, Kinuko Mitani, Toshiyuki Kitano, Nobuyoshi Arima, Yukiharu Nakabo, Nobuo Sezaki, Nobuhiro Kanemura, Takahiro Fukuda, Motoshi Ichikawa, Yasushi Miyazaki, Shigeo Fuji, Mamiko Sakata-Yanagimoto, Yoshinori Yoshida, Akifumi Takaori-Kondo, Seishi Ogawa, Yasuhito Nannya.
      NUP98 rearrangements represent a distinct, high-risk subtype of acute myeloid leukemia (AML), particularly in pediatric patients. However, their prevalence, genetic features, and clinical implications in adult AML remain poorly characterized. Using targeted-capture sequencing, we identified 41 cases with NUP98 rearrangements among 1569 AML cases, representing the majority of 44 NUP98-rearranged cases detected across 4753 myeloid neoplasms. Fifteen distinct fusion partners were detected, with NUP98::NSD1 and NUP98::HOXA9 being the most frequent. Notably, two novel fusions-NUP98::MEOX2 and NUP98::HOXA6-were identified. Co-mutations were relatively infrequent; FLT3-ITD and WT1 mutations were the most common, while NPM1 mutations were exclusive. FLT3-ITD was significantly enriched in NUP98::NSD1 cases, whereas TET2 mutations were more frequent in NUP98::HOXA9 cases. Clonal hierarchy analysis suggested that NUP98 rearrangements occur early in leukemogenesis. NUP98-rearranged AML exhibited higher relapse rates and shorter event-free survival. Specifically, NUP98::NSD1 was associated with a poor induction response, whereas NUP98::HOXA9 and NUP98 fusions with other partners showed higher remission rates but frequent relapse. Allogeneic hematopoietic stem cell transplantation was associated with better survival, underscoring its significance. These findings reveal the genetic and clinical heterogeneity of NUP98-rearranged AML in adults and support its classification as a distinct entity, highlighting the need for fusion partner-specific therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41375-025-02848-4
  28. Res Sq. 2025 Dec 17. pii: rs.3.rs-8370111. [Epub ahead of print]
    Structural and Functional Analysis of GGPPS Inhibition as a Therapeutic Mechanism for Acute Myeloid Leukemia (AML).
    Youla Tsantrizos, Fraser Ferens, Daniel Waller, Rebecca Boutin, Hiu-Fung Lee, Marc Saba-El-Leil, Mathieu Tremblay, Tian Lai Guan, Kathryn Skorey, Michael Sebag, Arun Wiita, M Joanne Lemieux.
      Acute myeloid leukemia (AML) is a hematological malignancy with poor treatment outcomes and high mortality rates. AML progression is influenced by signalling events facilitated by small GTPases anchored to cellular membranes via post-translational modification with geranylgeranyl pyrophosphate (GGPP). The disruption of GGPP biosynthesis, and the resulting intracellular reduction of key geranylgeranylated GTPases, represents an as yet unleveraged strategy for the treatment of cancer. Here we show compound CML-07-119, a selective inhibitor of GGPP synthase (GGPPS), to display an EC 50 potency in the nanomolar range and to induce targeted cell death in several AML cell lines, including those harbouring TP53 mutations. Antitumor efficacy in vivo was also observed with CML-07-119 in a mouse xenograft model engrafted with AML NOMO-1 cells, equivalent to the drug cytarabine. Bone-marrow and splenocyte cells harvested from mice treated with CML-07-119 displayed significantly higher concentration of unprenylated RAP1A as compared to the controls, demonstrating the expected biochemical outcome of in vivo GGPPS inhibition. X-ray crystallography and cryo-EM were used to determine high resolution structures of the unliganded GGPPS and the GGPPS/CML-07-119 complex. These structures revealed that the inhibitor occupies a previously proposed product inhibitory channel of the enzyme, and modulates previously unknown conformational states of GGPPS quaternary structure. This work validates GGPPS inhibition as potential novel mechanism for the treatment of AML.
    DOI:  https://doi.org/10.21203/rs.3.rs-8370111/v1
  29. Cell Death Dis. 2026 Jan 09.
    ATGL suppresses ferroptosis in acute myeloid leukemia cells by modulating the CEBPα/SCD1 axis and induces gilteritinib resistance.
    Shiyi Yuan, Ying Zhou, Wenrui Xiao, Ning Liu, Ping Zhang, Ying Zhang, Jianchuan Deng, Liang Fang, Xi Zhang, Shifeng Lou.
      Metabolic reprogramming disrupts energy homeostasis and promotes tumor cell proliferation. In the present study, high expression of adipose triglyceride lipase (ATGL) in patients with acute myeloid leukemia (AML) predicted a poor clinical prognosis. Furthermore, the aberrant upregulation of ATGL was confirmed to promote the malignant progression of AML through gene ablation, overexpression, and pharmacological inhibition of ATGL, particularly in FLT3-ITD-mutated AML. RNA sequencing, lipid peroxidation, cellular iron, and ROS assays were performed to confirm the association of ATGL with ferroptosis. Mechanistically, ATGL is positively correlated with stearoyl-CoA decarboxylase 1 (SCD1) and promotes the malignant progression of AML by inhibiting ferroptosis through the CEBPα/SCD1 axis. We established gilteritinib-resistant MOLM-13 and MV4-11 cell lines and collected cells from patients with FLT3-ITD mutations to confirm that ATGL inhibitors increased the efficacy of gilteritinib. Consequently, we constructed an AML xenograft model using cells derived from patients with FLT3-ITD-mutated AML to confirm the efficacy of combining ATGL inhibitors with gilteritinib in vivo. This study provides novel therapeutic targets and monitoring indicators for AML, along with new treatment strategies for patients with FLT3-ITD-mutated AML and those with relapsed/refractory FLT3-ITD-mutated AML.
    DOI:  https://doi.org/10.1038/s41419-025-08388-0
  30. iScience. 2026 Jan 16. 29(1): 114327
    Prognostic value of BTG1 for predicting decitabine sensitivity in de novo acute myeloid leukemia.
    Shiyuan Zhang, Mengyuan Li, Bin Xu, Xiaojian Zhu, Xia Mao, Hao Zhou, Xiwen Tong, Shuai Su, Yi Zhu, Donghua Zhang.
      Decitabine has demonstrated efficacy in the treatment of acute myeloid leukemia (AML), though therapeutic responses vary widely due to the disease's inherent heterogeneity. To address this clinical challenge, we aimed to identify reliable biomarkers for predicting decitabine responsiveness in patients with AML. In our previous studies, integrated epigenetic and transcriptomic profiling identified BTG1 as a methylation-associated tumor suppressor gene correlated with decitabine sensitivity. We found that decitabine upregulates BTG1 expression through demethylation, and this upregulation enhances the sensitivity of AML cells to decitabine. BTG1 may exert its effect through the Wnt/β-catenin signaling pathway. Notably, BTG1 expression levels were significantly associated with treatment outcomes, including complete remission (CR) rates and measurable residual disease (MRD) negativity in patients receiving decitabine-containing regimens (either "7 + 3" or alternative combinations). Importantly, peripheral blood BTG1 mRNA expression levels reliably predicted therapeutic response to decitabine, establishing BTG1 as a robust biomarker of decitabine efficacy in AML management. Clinical trial registration: ChiCTR2000037928.
    Keywords:  Cancer; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2025.114327
  31. Leukemia. 2026 Jan 07.
    Sequential BCR::ABL1 evaluation during dose de-escalation in peripheral blood is more predictive of TFR success than single assessment at dose de-escalation in either peripheral blood or bone marrow.
    S D Patterson, A Gottschalk, C Hayden, R Young, A Hair, H G Jørgensen, H W Wheadon, J F Apperley, I Glauche, R E Clark, M Copland, I Roeder.
      
    DOI:  https://doi.org/10.1038/s41375-025-02853-7
  32. Blood. 2026 Jan 09. pii: blood.2025028645. [Epub ahead of print]
    Next-Generation JAK Inhibitors in the Treatment of Myeloproliferative Neoplasms.
    Stefan N Constantinescu, William Vainchenker, Christian Pecquet.
      JAK inhibitors have changed the treatment landscape of myeloproliferative neoplasms, graft-versus host and several autoimmune conditions. While approved JAK inhibitors generally target the JAK2 kinase domain, and several also the JAK1 kinase domain in active form (type I inhibition), new inhibitors have progressed to clinical trials that either exhibit a type II mechanism of inhibition of the kinase domain in an inactive state or that target the pseudokinase domain with potential preference or specificity for the JAK2 V617F mutant. This is the most prevalent mutant in myeloproliferative neoplasms. An ideal inhibitor would target persistently activated JAK2 in MPNs, eradicate the clone or induce deep molecular remission in addition to clinical and hematological remission and spare wild type JAK2 that is critical for hematopoiesis and immune response. We discuss perspectives of these and other modes of JAK inhibition and primary as well as secondary/exploratory study endpoints in clinical trials design, along with potential biomarker correlates to evaluate potential efficacy of the next generation versus conventional JAK inhibitors.
    DOI:  https://doi.org/10.1182/blood.2025028645
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