bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2026–04–12
47 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Genotype-immunophenotype relationships in NPM1-mutated AML clonal evolution uncovered by single-cell multiomic analysis.
  2. CPX-351 (Liposomal Cytarabine and Daunorubicin) versus venetoclax plus hypomethylating agent therapy in newly diagnosed acute myeloid leukemia: a retrospective comparison involving 600 Mayo Clinic patients.
  3. Unraveling the role of TP53 mutations in myeloproliferative neoplasms: Molecular mechanisms of leukemic transformation.
  4. Overcoming MEN1-mediated resistance with menin inhibitor switching in KMT2A-rearranged acute myeloid leukemia.
  5. Late outcomes after posttransplant cyclophosphamide-based GVHD prophylaxis in patients with AML: an ALWP-EBMT study.
  6. Treatment-specific prognostic performance of ELN 2022, ELN 2024, and Beat AML 2024: a real-world AML validation study.
  7. PITPβ Drives JAK2 V617F-Mediated Myeloproliferative Neoplasms by Promoting PtdIns(3,4)P ₂ -Dependent AKT Hyperactivation.
  8. Quizartinib in newly diagnosed patients with FLT3-ITD-positive AML who received maintenance therapy in QuANTUM-First.
  9. Polycomb repressive complex 2 insufficiency underlies myeloid leukemia in Down syndrome.
  10. Understanding drug resistance in chronic myeloid leukemia through the lens of leukemic stem cell states: insights from single-cell analyses.
  11. One vs. 2 vs. ≥3 TET2 mutations in chronic myelomonocytic leukemia: co-mutation patterns and prognostic relevance in the context of contemporary prognostic models including BLAST-mol and CPSS-mol.
  12. Contrasting impacts of pretransplant cytoreduction and post-transplant maintenance on outcomes of allogeneic haematopoietic stem cell transplantation in myelodysplastic syndromes: Real-world multicentre evidence.
  13. Management of tyrosine kinase inhibitors and donor lymphocyte infusions post transplantation for chronic myeloid leukemia: a survey of contemporary practice on behalf of the chronic malignancies working party of the EBMT.
  14. Fetal-restricted hematopoietic progenitors arise from hemogenic endothelium in vitelline and umbilical arteries.
  15. Mutation-specific impairment of TET2 and DNMT3A enzymatic activity predicts clonal hematopoiesis disease risk.
  16. Haploidentical transplantation with post-transplant cyclophosphamide is not inferior to 9/10-MUD transplantation with ATG in patients with myeloid malignancies.
  17. Apoptotic modulators enhance oncolytic virus-induced cytokine killing in acute myeloid leukaemia (AML).
  18. Combined Menin and XPO1 inhibition drive synergistic antileukemic activity in KMT2A r and NPM1 -m AML.
  19. Association between treatment-emergent cytopenias and clinical responses to imetelstat in lower-risk myelodysplastic syndromes.
  20. DLK1 is a GATA1s-Driven Dependency and Therapeutic Target in Down Syndrome-Associated Myeloid Leukemia.
  21. MYB activity drives emergent enhancer activation and enhancer-promoter interactions in acute lymphoblastic leukemia.
  22. Nonsense-Mediated RNA Decay is a Targetable Vulnerability in Splicing Factor Mutant Myeloid Neoplasms by Enhancing R-loop Accumulation and DNA Damage.
  23. Myeloid/lymphoid precursor cell neoplasms and mixed phenotype acute leukemias: A Bone Marrow Workshop Report from the 22nd European Association for Hematopathology/Society of Hematopathology Meeting, Dubrovnik, 2024.
  24. Disease course of FLT3 mutated extramedullary acute myeloid leukemia and efficacy of gilteritinib.
  25. RPS19 and RPL5 haploinsufficient models reveal divergent ribosomal subunit controls of fetal hematopoiesis.
  26. Response to therapy and prognosis according to molecular characterization in CALR-mutated essential thrombocythemia.
  27. A paradigm shift in the treatment of patients with polycythemia vera. The initial early use of recombinant interferon-alpha.
  28. Non-necroptotic MLKL function damages mitochondria and promotes hematopoietic stem cell aging.
  29. First-in-Human Study of IL15-Activated Cytokine-Induced Killer Cells After Allogeneic HCT Shows Durable Remission and Serotherapy-Associated Immune Reconstitution in Leukemia.
  30. Glutamine addiction is a therapeutic target to block emergency myelopoiesis.
  31. Quizartinib and omacetaxine mepesuccinate combination therapy in FLT3-ITD AML: a phase II trial.
  32. The ASH HematOmics Program supports integrative analysis of genomic and clinical data in hematologic diseases.
  33. Eligibility is not appropriateness: Reframing the role of age in allogeneic transplant decision-making.
  34. Stem cell function in vivo is supported by an alternative glycolysis endpoint.
  35. Erdheim-Chester disease associated with myeloid neoplasm: Clinical features, molecular landscape, and treatment outcomes.
  36. Concomitant or sequential lower intensity triplet therapy in AML.
  37. A multimodal atlas for immunotherapeutic targeting of AML surface heterogeneity.
  38. 5-Azacytidine incorporation into mRNAs disrupts translation and induces ribosome collisions.
  39. Nuclear Transcriptional Condensates as Drivers and Therapeutic Targets in NPM1-mutated AML.
  40. A phase I, single-arm, open-label, dose-escalation, multicenter study of SAR445419, an off-the-shelf, ex vivo expanded allogeneic natural killer cell product, in participants with relapsed or refractory acute myeloid leukemia.
  41. Trends in survival outcomes after allogeneic transplantation for MDS and MDS/MPN in a real-world experience: A 25-year nationwide study.
  42. Sialylated CD43 forms a glyco-immune barrier that restrains antileukemic immunity.
  43. Structure-guided design of 7-azaindole DNMT1 inhibitors active against hypomethylating agent-resistant acute myeloid leukemia.
  44. Mitochondrial transfer in acute myeloid leukaemia and multiple myeloma: Mechanisms, consequences and potential therapeutic opportunities.
  45. Changes in neutrophil-to-lymphocyte ratio in patients with polycythemia vera treated with ruxolitinib reflect JAK2 variant allele frequency.
  46. The rise of bone marrow organoids as next-generation models for blood formation and failure.
  47. Phase 1 Study of KITE-222, an Autologous CLL-1-directed CAR T-cell Therapy in Patients With Relapsed/Refractory Acute Myeloid Leukemia.
  1. Blood. 2026 Apr 08. pii: blood.2025030772. [Epub ahead of print]
    Genotype-immunophenotype relationships in NPM1-mutated AML clonal evolution uncovered by single-cell multiomic analysis.
    Morgan Drucker, Darren Lee, Michael S Bowman, Xuan Zhang, Bailee Nicole Kain, Deedra Nicolet, Roopsha Bandopadhyay, Varsha Singh, Zhe Wang, Richard M Stone, Caner Saygin, Krzysztof Mrózek, Andrew J Carroll, Daniel T Starczynowski, Ross L Levine, John C Byrd, Nathan Salomonis, Sarah J Skuli, H Leighton Grimes, Ann-Kathrin Eisfeld, Robert L Bowman, Linde A Miles.
      Acute myeloid leukemia (AML) is a multi-clonal disease, existing as a milieu of clones with unique but related genotypes as initiating clones acquire subsequent mutations. However, bulk sequencing cannot fully capture AML clonal architecture or the clonal evolution that occurs as patients undergo therapy. To interrogate clonal evolution, we performed simultaneous single-cell molecular profiling and immunophenotyping on 43 samples from 32 NPM1-mutated AML patients at different timepoints in disease progression. Here we show that diagnosis and relapse AML samples display similar clonal architecture patterns, but signaling mutations drive increased clonal complexity, specifically at relapse that correlates with overall survival. We uncovered unique genotype-immunophenotype relationships regardless of disease state, suggesting leukemic lineage trajectories can be hard-wired by the mutations present. Analysis of longitudinal samples from patients on front-line AML therapy identified dynamic clonal and immunophenotypic changes consistent with the genotype-immunophenotype relationships we identified.
    DOI:  https://doi.org/10.1182/blood.2025030772
  2. Blood Cancer J. 2026 Apr 06.
    CPX-351 (Liposomal Cytarabine and Daunorubicin) versus venetoclax plus hypomethylating agent therapy in newly diagnosed acute myeloid leukemia: a retrospective comparison involving 600 Mayo Clinic patients.
    Saubia Fathima, Lior Rokach, Nour Ghosoun, Mahsa Rezasoltani, Rimal Ilyas, Ali Alsugair, Kristen McCullough, Maymona Abdelmagid, Aref Al-Kali, Hassan B Alkhateeb, Kebede H Begna, Abhishek A Mangaonkar, Aasiya Matin, Antoine N Saliba, Mehrdad Hefazi Torghabeh, Mark R Litzow, William Hogan, Mithun Shah, Mrinal M Patnaik, Animesh Pardanani, Talha Badar, Hemant Murthy, James Foran, Jeanne Palmer, Nathan Punwani, Lisa Sproat, Nandita Khera, Cecilia Arana Yi, Ayalew Tefferi, Naseema Gangat.
      The comparative value of liposomal cytarabine/daunorubicin (CPX-351) versus venetoclax plus a hypomethylating agent (Ven-HMA) in the frontline treatment of older adults with primary (de novo) or secondary acute myeloid leukemia (AML) remains uncertain. In the current study, we retrospectively examined outcomes of 600 patients with newly diagnosed AML treated with CPX-351 (N = 112) or Ven-HMA (N = 488). AML subtypes included de novo (N = 277, 46%), post-myelodysplastic syndrome (post-MDS, N = 114,19%), post-myeloproliferative neoplasm (post-MPN, N = 70, 12%), post-MDS/MPN (N = 36, 6%), and t-AML (N = 103, 17%). Patients receiving CPX-351 were younger (median 65 vs. 73 years; p < 0.01), predominantly female (50% vs. 38%; p = 0.02), more likely to have secondary AML (68% vs. 51%; p < 0.01), and less likely to harbor NPM1MUT (5% vs. 12%; p = 0.02). Rates of complete response with or without count recovery (CR/CRi) were comparable between CPX-351 and Ven-HMA (55% vs. 60%; p = 0.30), including AML with myelodysplasia-related gene mutations or cytogenetic abnormalities (AML-MR 60% vs. 63%; p = 0.70). Ven-HMA use was associated with fewer infectious complications (62% vs. 83%; p < 0.01) and yielded higher CR/CRi rates in males (60% vs. 45%; p = 0.04), de novo AML (68% vs. 50%; p = 0.03), and in the presence of STAG2MUT (86% vs. 44%; p = 0.02), or CEBPAMUT (88% vs. 50%; p = 0.03). Overall survival censored for transplant, was similar (median 10 vs. 13 months; p = 0.90), with Ven-HMA being superior in post-MDS AML (median 12 vs. 7 months; p = 0.02) and CPX-351 in the presence of SF3B1MUT (median not reached vs. 14 months; p < 0.01). Our findings suggest that Ven-HMA is as effective and less toxic than CPX-351 in newly diagnosed AML, including AML-MR, despite selection of younger, fitter patients for CPX-351.
    DOI:  https://doi.org/10.1038/s41408-026-01495-x
  3. Hemasphere. 2026 Mar;10(3): e70332
    Unraveling the role of TP53 mutations in myeloproliferative neoplasms: Molecular mechanisms of leukemic transformation.
    Suzana da Silva-Benedito, Paula Sabbo Bernardo, Jean-Edouard Martin, Caroline Marty, Isabelle Plo, Iléana Antony-Debré, Bárbara da Costa Reis Monte-Mór.
      TP53 mutations are found in over 50% of tumor types, including myeloproliferative neoplasms (MPNs). MPNs are characterized by a chronic phase, which may progress to secondary acute myeloid leukemia (sAML). Here, we discuss the physiological functions of p53 in hematopoiesis and its deregulation in MPNs. Additionally, we explore the mechanisms underlying TP53 mutations in the leukemic transformation of MPNs, including clonal evolution to multihit status and the role of inflammation and therapy. Finally, recent findings on the clinical impact of multihit TP53 mutations and potential strategies for targeting the p53 pathway in MPNs and sAML are presented.
    DOI:  https://doi.org/10.1002/hem3.70332
  4. Leukemia. 2026 Apr 10.
    Overcoming MEN1-mediated resistance with menin inhibitor switching in KMT2A-rearranged acute myeloid leukemia.
    Kuo-Kai Chin, Maher Abdul-Hay, Mihir Shukla, Mark B Geyer, Roni Tamari, Kaitlyn H Ko, Wenbin Xiao, Eytan M Stein, Sheng F Cai.
      
    DOI:  https://doi.org/10.1038/s41375-026-02959-6
  5. Blood Neoplasia. 2026 May;3(2): 100199
    Late outcomes after posttransplant cyclophosphamide-based GVHD prophylaxis in patients with AML: an ALWP-EBMT study.
    Eduardo Rodríguez-Arbolí, Allain-Thibeault Ferhat, Anna Maria Raiola, Linde Morsink, Didier Blaise, Jurjen Versluis, Simona Sica, Mi Kwon, Lucía López-Corral, Erfan Nur, Alexander Kulagin, Stefania Bramanti, Montserrat Rovira, Edouard Forcade, Massimo Martino, Jan Vydra, Simona Piemontese, Jaime Sanz, Mohamad Mohty, Fabio Ciceri.
      Data on late events after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with posttransplant cyclophosphamide (PT-Cy)-based graft-versus-host disease (GVHD) prophylaxis in patients with acute myeloid leukemia (AML) remain very limited. We analyzed long-term outcomes in 1289 patients from the European Society for Blood and Marrow Transplantation registry who underwent PT-Cy-based allo-HSCT for AML in first remission from haploidentical (n = 906), 10/10 matched unrelated donors (MUD, n = 208), or matched sibling donors (MSD, n = 175), and who remained leukemia-free 2 years after transplantation. At 2 years from the landmark, the cumulative incidence of relapse and nonrelapse mortality (NRM) was 6% and 4% in haploidentical, 7% and 3% in MUD, and 8% and 4% in MSD recipients, respectively. Similarly, 2-year estimates of leukemia-free survival and overall survival were 91% and 93% for haploidentical, 90% and 95% for MUD, and 88% and 93% for MSD recipients, respectively. No statistically significant association was found between donor type and long-term transplantation outcomes. In contrast, transplantation from a female donor to a male recipient (hazard ratio [HR], 2.70; P = .013) and older donor age (HR per 10-year increase, 1.34; P = .036) were associated with increased risk of late NRM. These associations were confirmed in subanalyses in the haploidentical cohort. Notably, no factors associated with late relapse were identified in the multivariable models. PT-Cy-based allo-HSCT is associated with favorable outcomes in patients with AML who remain leukemia-free 2 years after transplant. Long-term outcomes after haploidentical allo-HSCT were comparable with those of 10/10 MUD or MSD recipients in the setting of PT-Cy GVHD prophylaxis.
    DOI:  https://doi.org/10.1016/j.bneo.2026.100199
  6. Blood Neoplasia. 2026 May;3(2): 100212
    Treatment-specific prognostic performance of ELN 2022, ELN 2024, and Beat AML 2024: a real-world AML validation study.
    Tariq Kewan, Oudai Alkabbani, Hadil Zureigat, Rong He, Dragan Jevremovic, Patricia Greipp, Antoine Saliba, Aasiya Matin, Mehrdad Hefazi Torghabeh, Abishek Mangaonkar, Naseema Gangat, William Hogan, Mrinal Patnaik, Hassan Alkhateeb, Cecilia Arana Yi, James Foran, Mark Litzow, Mithun Shah, Kebede Begna, Aref Al-Kali.
      Real-world validation of the European LeukemiaNet (ELN) 2022, ELN 2024, and Beat Acute Myeloid Leukemia (AML) 2024 across different therapies is needed. We evaluated 426 patients with AML (median age, 68 years; 60% male) treated from 2016 to 2025. ELN 2024 (55%, 24%, and 20%), ELN 2022 (20%, 20%, and 60%), and Beat AML 2024 (21%, 38%, and 41%) assigned patients to favorable-, intermediate-, and adverse-risk groups with variation. Less-intensive treatment (LIT) had lower complete remission (CR) odds than intensive chemotherapy (IC). For CR prediction, ELN 2022 (area under the receiver operating characteristic curve [AUC], 0.763) and Beat AML 2024 (AUC, 0.759) outperformed ELN 2024 (AUC, 0.718). With a median follow-up of 49.8 months, the median overall survival (mOS) was 15.7 months. Each system stratified mOS (all P < .001); overall c-index favored ELN 2022 (0.640) and Beat AML 2024 (0.635) over ELN 2024 (0.601). For patients treated with IC, ELN 2022 (0.680) and Beat AML 2024 (0.664) exceeded ELN 2024 (0.601); for patients treated with LIT, ELN 2024 and Beat AML 2024 identified a favorable group with better mOS, whereas ELN 2022 failed to discriminate between favorable and intermediate risk. Allogeneic hematopoietic stem cell transplantation improved mOS; in time-dependent analysis, adverse risk by Beat AML 2024 (hazard ratio [HR], 4.0), ELN 2024 (HR, 3.0), and ELN 2022 (HR, 2.5) remained independently unfavorable. Overall, Beat AML 2024 was the most informative in IC, and ELN 2024/Beat AML 2024 better identified favorable patients in LIT.
    DOI:  https://doi.org/10.1016/j.bneo.2026.100212
  7. bioRxiv. 2026 Mar 30. pii: 2026.03.26.714558. [Epub ahead of print]
    PITPβ Drives JAK2 V617F-Mediated Myeloproliferative Neoplasms by Promoting PtdIns(3,4)P ₂ -Dependent AKT Hyperactivation.
    Nikita A Vantsev, Liang Zhao, Shin Morioka, Hiroaki Kajiho, Junko Sasaki, Takehiko Sasaki, Charles S Abrams, Wei Tong.
      JAK2 is a key regulator of cytokine-mediated proliferative signaling in hematopoietic stem and progenitor cells. Activating mutations, most commonly JAK2 V617F, trigger aberrant cytokine signaling driving the pathogenesis of myeloproliferative neoplasms (MPNs). Phosphatidylinositol transfer proteins (PITPs) facilitate phosphoinositide synthesis by delivering phosphatidylinositol to lipid kinases, though their roles in oncogenic signaling have remained poorly defined. Here we show that PITPβ is critical for the development of JAK2V617F-driven MPN in mice. Deleting Pitp β across the hematopoietic system, but not Pitp α, prolonged 25-week survival of Jak2V617F mice from 10% to 85%. Loss of Pitp β attenuated disease-associated splenomegaly and curtailed erythroid progenitors expansion both in vivo and in vitro . Mechanistically, PITPβ is necessary for AKT hyperactivation in hematopoietic progenitors, while STAT5 and ERK signaling remain unaffected. In alignment with this role, PITPβ promotes the production of PtdIns(3,4)P ₂ , a phosphoinositide that sustains aberrant AKT signaling in Jak2V617F progenitors. Pharmacologic inhibition of AKT with the FDA-approved inhibitor capivasertib in Jak2V617F-transplanted mice similarly reduced splenomegaly and erythroid proliferation, mimicking the effects of Pitp β loss. Collectively, these results identify a novel PITPβ-PtdIns(3,4)P ₂ signaling axis that selectively maintains pathological AKT activation in JAK2V617F-driven MPN, revealing a promising therapeutic vulnerability.
    DOI:  https://doi.org/10.64898/2026.03.26.714558
  8. Blood Adv. 2026 Apr 08. pii: bloodadvances.2025017738. [Epub ahead of print]
    Quizartinib in newly diagnosed patients with FLT3-ITD-positive AML who received maintenance therapy in QuANTUM-First.
    Mark J Levis, Harry P Erba, Pau Montesinos, Elzbieta Patkowska, Jorge E Cortes, Alexander E Perl, Hervé Dombret, Sergio Amadori, Jianxiang Wang, Richard F Schlenk, Li Liu, Yasser Mostafa Kamel, Karima Imadalou, Abderrahmane Laadem, Kristy Burns, Mikkael A Sekeres.
      QuANTUM-First (NCT02668653) demonstrated improved overall survival (OS) in FLT3-ITD-positive patients with newly diagnosed acute myeloid leukemia (ndAML) treated with quizartinib plus standard chemotherapy. Herein, we evaluated the impact of post-consolidation/post-transplant single-agent maintenance therapy on clinical outcomes in patients receiving maintenance, focusing on measurable residual disease (MRD) status at maintenance onset. Overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS) were prespecified exploratory analyses. Cumulative incidence of relapse (CIR), analyses by allogeneic hematopoietic stem cell transplant (allo-HCT), and analyses by MRD status were post-hoc and not powered for statistical significance. Samples for FLT3-ITD MRD analysis were collected in composite complete remission patients ≤30 days before receiving maintenance and assessed by an ultrasensitive amplicon-based assay. More transplanted quizartinib-treated patients received maintenance (71%) vs placebo (55%); OS benefit was not demonstrated among these patients. In patients who did not undergo allo-HCT, quizartinib maintenance was associated with a significant OS benefit (HR 0.401; 95% CI, 0.192-0.838), including a benefit in patients who were MRD-negative at the start of maintenance (OS HR of 0.194, 95% CI, 0.056-0.676). Patients who were MRD-negative at the completion of consolidation achieved 89.1% (95% CI, 70.0%-96.4%) survival at 3 years with quizartinib maintenance in the absence of allo-HCT. These data suggest that for patients who achieve FLT3-ITD MRD negativity after induction and consolidation with quizartinib, maintenance with quizartinib provides a significant survival benefit and in some patients may eliminate the need for allo-HCT.
    DOI:  https://doi.org/10.1182/bloodadvances.2025017738
  9. Blood. 2026 Apr 08. pii: blood.2025032083. [Epub ahead of print]
    Polycomb repressive complex 2 insufficiency underlies myeloid leukemia in Down syndrome.
    Yutaro Suzuki, Yaeko Nakajima-Takagi, Motohiko Oshima, Yotaro Ochi, Akiho Tsuchiya, Shuhei Koide, Takako Yokomizo-Nakano, Shuhei Kurosawa, Ola Rizq, Ayana Kon, Satoru Miyano, Bahityar Rahmutulla, Atsushi Kaneda, Manabu Nakayama, Haruhiko Koseki, Eugene Yu, Tsutomu Toki, Etsuro Ito, Seishi Ogawa, Atsushi Iwama.
      Children with Down syndrome (DS) have an elevated risk of developing myeloid leukemia in DS (ML-DS). In addition to mutations in GATA1, which generate the truncated isoform GATA1-short (GATA1s), ML-DS requires additional somatic gene mutations, most frequently in cohesion and polycomb repressive complex 2 (PRC2) genes. Here, we show that PRC2 insufficiency underlies ML-DS pathogenesis. Transplantation of Gata1s fetal liver cells followed by deletion of the cohesion subunit Stag2 and/or the PRC2 component Ezh2 induced megakaryocyte-biased differentiation and expansion of megakaryocytic progenitors, culminating in lethal myelofibrosis. Mechanistically, loss of Stag2 or Ezh2 reinforced Gata1s-driven reduced chromatin accessibility at erythroid transcription factor target loci in pre-megakaryocyte/erythroid progenitors (pre-MegEs), thereby promoting megakaryocytic skewing. Ezh2 loss attenuated the Gata1s-mediated global elevation of H3K27me3 in pre-MegEs, resulting in derepression of a broad set of PRC2 target genes and establishing a functionally PRC2-insufficient state. Similarly, Stag2 loss induced a moderate but significant degree of PRC2-insufficient state in Gata1s progenitors. Furthermore, chromosome 21-encoded miR-125b blocked megakaryocytic differentiation of Gata1s progenitors lacking either Stag2 or Ezh2 alone, but drove full transformation and expansion of CD150+Sca-1+c-Kit+ leukemic stem cell-like populations only upon concurrent loss of both Stag2 and Ezh2, leading to acute megakaryoblastic leukemia in mice. These findings reveal that cohesin and PRC2 insufficiencies converge on PRC2 dysfunction while exerting distinct epigenetic effects, and synergize with trisomy 21 and GATA1s to remodel the epigenetic landscape, driving progression from a preleukemic state to overt leukemia.
    DOI:  https://doi.org/10.1182/blood.2025032083
  10. Haematologica. 2026 Apr 09.
    Understanding drug resistance in chronic myeloid leukemia through the lens of leukemic stem cell states: insights from single-cell analyses.
    Vaidehi Krishnan, Pavithra Shyamsunder, Tiong S Ong.
      Despite the advent of potent tyrosine kinase inhibitors (TKIs), resistance and disease persistence remain significant clinical challenges in chronic myeloid leukemia (CML). This perspective aims to synthesize concepts derived from recent advances in single-cell and multi-omics analyses, which have revealed profound heterogeneity among leukemic stem cells (LSCs). These findings augment traditional models that focus solely on clonal selection and resistance-conferring mutations. We discuss how LSCs, like normal hematopoietic stem cells (HSCs), exist in a spectrum of transcriptionally and epigenetically defined cell states, each governed by distinct gene regulatory networks (GRNs) that confer unique lineage biases and responses to therapy. Incorporating recent insights from single-cell analysis, our perspective highlights evidence for a conserved chronic phase (CP) LSC state characterized by lineage skewing, altered metabolic and environmental responsiveness, and epigenetic dysregulation, features that are likely to be underpinned by specific GRN configurations that collectively contribute to intrinsic TKI resistance. We explore how both intrinsic factors (such as germline polymorphisms and lineage bias) and extrinsic cues (including microenvironmental signals, immune interactions, and hypoxia) are likely to modulate GRN activity and LSC states, thereby affecting apoptotic thresholds, primary resistance, and the potential for treatment-free remission (TFR). Emerging data support the concept of GRNdefined LSC states at diagnosis that are predictive of TKI responses. Furthermore, multiple studies suggest that blast crisis (BC) converges on a common high-risk transcriptomic and GRN state that is agnostic to mutational diversity, and driven by polycomb and DNA methylation-dependent epigenetic reprogramming. Given that BCR::ABL1-independent mechanisms, regulated at the level of GRNs, may contribute to resistance and LSC persistence, these observations support placing greater emphasis in CML management on addressing GRN-defined cell-state vulnerabilities, with the goal of lowering the risk of blast crisis in high-risk patients and improving control of therapy-resistant CP LSCs.
    DOI:  https://doi.org/10.3324/haematol.2025.287767
  11. Blood Cancer J. 2026 Apr 04. pii: 54. [Epub ahead of print]16(1):
    One vs. 2 vs. ≥3 TET2 mutations in chronic myelomonocytic leukemia: co-mutation patterns and prognostic relevance in the context of contemporary prognostic models including BLAST-mol and CPSS-mol.
    Muhammad Yousuf, Saubia Fathima, Ali Khalid A Alsugair, Samuel J Wu, Maymona G Abdelmagid, Shraddha P Patel, Priyansh C Faldu, Rania M Abdelaziz, Clifford M Csizmar, Abhishek A Mangaonkar, Cinthya J Zepeda Mendoza, Kaaren K Reichard, David S Viswanatha, Rong He, Animesh Pardanani, Naseema Gangat, Mrinal S Patnaik, Ayalew Tefferi.
      
    DOI:  https://doi.org/10.1038/s41408-026-01500-3
  12. Br J Haematol. 2026 Apr 10.
    Contrasting impacts of pretransplant cytoreduction and post-transplant maintenance on outcomes of allogeneic haematopoietic stem cell transplantation in myelodysplastic syndromes: Real-world multicentre evidence.
    Yilin Chen, Xiaotong Zhang, Na Shen, Jianguang Zhang, Rong Guo, Haizhou Xing, Lijie Han, Yi Liu, Wenliang Tian, Meng Wang, Xinsheng Xie, Zhongxing Jiang, Dingming Wan, Xuefang Zhou, Huili Xu, Ling Qin, Wei Shi, Weijie Cao, Zhilei Bian.
      Allogeneic haematopoietic stem cell transplantation (allo-HSCT) remains the only curative therapy for patients with high-risk myelodysplastic syndrome (MDS). However, the optimal timing and value of pretransplant cytoreduction and post-transplant maintenance remain unclear, and transplant-modifiable variables are not well defined in real-world settings. We retrospectively analysed 215 consecutive MDS patients who underwent allo-HSCT. Clinical, molecular and transplant-related factors were evaluated for their impact on relapse, relapse-free survival (RFS) and overall survival (OS). TP53 mutation, complex karyotype, and positive measurable residual disease (MRD) after cytoreductive treatment were associated with increased relapse risk. Among transplant-related variables, younger donor age (<42 years) and higher CD34+ cell dose (≥3.1 × 106/kg) significantly reduced relapse risk. Notably, pretransplant cytoreduction did not confer measurable benefit on outcomes. In contrast, post-transplant maintenance therapy significantly reduced relapse incidence and prolonged RFS. Pretransplant cytoreduction offers limited clinical value, whereas post-transplant maintenance and modifiable transplant variables (CD34+ cell dose and donor age) substantially improve outcomes after allo-HSCT for MDS. These findings highlight actionable strategies that may refine transplant decision-making and optimize outcomes in clinical practice.
    Keywords:  allogeneic haematopoietic stem cell transplantation; hypomethylating agents; myelodysplastic syndrome; pretransplant cytoreduction
    DOI:  https://doi.org/10.1111/bjh.70477
  13. Bone Marrow Transplant. 2026 Apr 10.
    Management of tyrosine kinase inhibitors and donor lymphocyte infusions post transplantation for chronic myeloid leukemia: a survey of contemporary practice on behalf of the chronic malignancies working party of the EBMT.
    Alexandros Kanellopoulos, Linda Koster, Hugues de Lavallade, Guillermo Ortí, Sebastian Francis, Jakob Passweg, Jane Apperley, Wolfgang Bethge, Werner Rabitsch, Jennifer Clay, Edouard Forcade, Erin Hurst, Caroline Besley, Francesca Kinsella, Mahmoud Aljurf, He Huang, Aloysius Ho, Inken Hilgendorf, Goda Choi, Francis Ayuk, Helbig Grzegorz, Matthias Stelljes, Deborah Richardson, Elena Morozova, Witold Prejzner, Robert Zeiser, Christopher Armstrong, Kavita Raj, Joanna Drozd-Sokolowska, Yves Chalandon, Donal P McLornan.
      The landscape of Allogeneic Haematopoietic Cell Transplantation (allo-HCT) for Chronic Myeloid Leukaemia (CML) remains dynamic with the advent of tyrosine kinase inhibitors (TKIs). There remains an absence of widely agreed evidence-based guidelines for post-transplant monitoring and relapse management. To evaluate current real-world practices for 'high risk' CML, the CML subcommittee of the Chronic Malignancies Working Party (CMWP) of the European Blood and Marrow Transplantation (EBMT) society developed an electronic survey, which was distributed to 39 EBMT-registered transplant centres in April 2024. Centres were chosen based on CML allo-HCT activity. Twenty-three centres (59%) responded, providing clinical perspectives into pre-transplant chemotherapy regimens, TKI use, ABL1 kinase domain mutation analysis, post-transplant monitoring, and their practice regarding sequencing/ integration of TKIs with donor lymphocyte infusions (DLI). Most centres conduct monthly BCR::ABL1 transcript monitoring during the first three months post-transplant, transitioning to quarterly assessments upon achieving a deep molecular response. TKI maintenance is widely adopted across centres, with treatment duration guided by molecular response, and TKIs are generally preferred over DLI for managing molecular relapse. However, DLI remains a valid option for TKI-refractory chronic-phase (CP)-CML relapse. Survey findings illustrate significant heterogeneity in practice, offering insights to inform research aimed at improving allo-HCT outcomes in CML.
    DOI:  https://doi.org/10.1038/s41409-026-02862-9
  14. Nat Cardiovasc Res. 2026 Apr 08.
    Fetal-restricted hematopoietic progenitors arise from hemogenic endothelium in vitelline and umbilical arteries.
    Cristiana Barone, Giulia Quattrini, Alessandro Muratore, Giorgio Anselmi, Yurim Park, Naeema T Mehmood, Elena Morganti, Roberto Orsenigo, Filipa Timóteo-Ferreira, Anna Cazzola, Arianna Patelli, Thea Milanesi, Bianca Nesti, Francisca Soares-da-Silva, Matthew Nicholls, Gloria Zambelli, Mario Mauri, Silvia Bombelli, Sofia De Marco, Deborah D'Aliberti, Silvia Spinelli, Veronica Bonalume, Alison Domingues, Mahdieh Naghavi Alhosseini, Gianluca Sala, Arianna Colonna, Elisabetta D'Errico, Cristina D'Orlando, Cristina Bianchi, Roberto A Perego, Raffaella Meneveri, Ana Cumano, Silvia Brunelli, Marella F T R De Bruijn, Andrea Ditadi, Alessandro Fantin, Rocco Piazza, Emanuele Azzoni.
      Embryonic hematopoiesis involves successive waves of progenitors from distinct anatomical sites, but the origins and contributions of early hematopoietic stem and progenitor cells (HSPCs) remain incompletely defined. Here we use genetic fate mapping in mice to temporally label hemogenic endothelium (HE) subsets and track their progeny. We show that a wave of fetal-restricted HSPCs arises from HE in the vitelline and umbilical arteries between embryonic days 8.5 and 9.5, preceding the emergence of definitive hematopoietic stem cells. Lineage tracing, single-cell transcriptomic analyses and functional assays revealed that these progenitors are transient and distinct from erythro-myeloid progenitors, contribute extensively to fetal lympho-myelopoiesis but decline postnatally. Our findings reveal a previously unrecognized early HE wave as a key source of fetal-restricted HSPCs, refining the spatial-temporal understanding of layered hematopoiesis and informing developmental origins of blood cell diversity.
    DOI:  https://doi.org/10.1038/s44161-026-00793-8
  15. medRxiv. 2026 Apr 05. pii: 2026.04.03.26350108. [Epub ahead of print]
    Mutation-specific impairment of TET2 and DNMT3A enzymatic activity predicts clonal hematopoiesis disease risk.
    Yash Pershad, Kun Zhao, Joseph C Van Amburg, Robert W Corty, Alyssa C Parker, Alexander J Silver, Yara Almadani, Ashwin Kishtagari, Emily Hodges, Michael R Savona, J Brett Heimlich, Alexander G Bick.
      Clonal hematopoiesis of indeterminate potential (CHIP) driven by somatic mutations in TET2 and DNMT3A is present in >10% of adults over 60 and confers substantial risk for hematologic malignancy and cardiovascular disease, yet the majority of patients with CHIP do not progress to disease. Analyzing 1,020,538 individuals across three biobanks (UK Biobank, All of Us, BioVU), we show that a discrete subset of enzymatically disruptive mutations - TET2 loss-of-function variants and the DNMT3A R882 hotspot - account for the majority of clinical risk in these genes and exhibit the strongest clonal fitness advantage. Because DNMT3A and TET2 encode enzymes that modulate DNA methylation, we reasoned that peripheral blood methylation patterns should reflect the functional impact of individual mutations, enabling a direct readout of enzymatic dysfunction in CHIP patients. We developed and validated methylation-based activity scores for TET2 and DNMT3A as patient specific biomarkers that quantify enzymatic activity. These scores capture functional heterogeneity across mutation subtypes, predict disease risk comparably to clinical risk scores such as the Clonal Hematopoiesis Risk Score and the AHA PREVENT cardiovascular risk model. Integrating the activity score with the clinical models substantially improves prediction of incident cytopenia, myeloid neoplasm, and major adverse cardiovascular events. These findings establish that TET2 and DNMT3A CHIP pathogenicity is proportional to the degree of enzymatic disruption conferred by specific variants, and nominate methylation-based activity scores as a functional biomarker for individualized CHIP risk stratification and monitoring therapeutic response.
    DOI:  https://doi.org/10.64898/2026.04.03.26350108
  16. Bone Marrow Transplant. 2026 Apr 08.
    Haploidentical transplantation with post-transplant cyclophosphamide is not inferior to 9/10-MUD transplantation with ATG in patients with myeloid malignancies.
    German Registry for Hematopoietic Stem Cell Transplantation and cell Therapy, DRST
      The selection of the best available donor is crucial for patients' outcome after allogeneic stem cell transplantation (allo-SCT). In the absence of fully Human leucocyte antigen (HLA) -matched donors, mismatched unrelated donor (9/10-MUD) or haploidentical donor (haplo) can be considered. No consensus has been reached on the best alternative and large real-world data are warranted to support decisional processes. We compared the outcome of 1413 patients with myeloid malignancies undergoing allo-SCT from 9/10-MUD with anti-thymocyte-globulin (ATG) (n = 1134) or haplo with post-transplant cyclophosphamide (PT-Cy, n = 279) between 2009 and 2020 in 48 German centres. Donor type with related graft versus host disease (GvHD) prophylaxis showed in multivariable analysis no significant impact on acute GvHD development, both grade II-IV (HR 0.90, 95% CI 0.69-1.19, p = 0.469) and severe (HR 1.22, 95% CI 0.82-1.81, p = 0.319), nor on moderate to severe chronic GvHD (HR 0.78, 95% CI 0.59-1.03, p = 0.077). Moreover, no influence from donor type was observed on GVHD-relapse-free survival (HR 1.12, 95% CI 0.92-1.36, p = 0.227), progression-free survival (HR 1.2, 95% CI 0.95-1.51, p = 0.121), non-relapse mortality (HR 1.1, 95% CI 0.81-1.51, p = 0.542) and overall survival (HR 1.16, 95% CI 0.91-1.48, p = 0.235). Our real-world data demonstrate that haplo allo-SCT with PT-Cy is not inferior to 9/10-MUD allo-SCT with ATG.
    DOI:  https://doi.org/10.1038/s41409-026-02827-y
  17. Br J Cancer. 2026 Apr 10.
    Apoptotic modulators enhance oncolytic virus-induced cytokine killing in acute myeloid leukaemia (AML).
    Basem Askar, Samuel Heaton, Tyler Barr, Richard Baugh, Noura Alzamel, Stewart McConnell, Victoria A Jennings, Milene Volpato, Christy Ralph, Manish Jain, Richard J Kelly, Christopher Parrish, Fiona Errington-Mais.
       BACKGROUND: Approximately 3000 adult patients are diagnosed with AML in the UK each year. Current intensive treatments are not well-tolerated by elderly patients, and the 5-year survival rate is only 5-15%, highlighting the need for novel and effective therapies. Oncolytic viruses (OVs) preferentially replicate in cancer cells, resulting in direct oncolysis and induction of innate and adaptive anti-tumour immunity. Unfortunately, the efficacy of OVs remains relatively unexplored in AML.
    METHODS: Using human AML cell lines, healthy-donor peripheral blood mononuclear cells (PBMC) and AML patient samples, we investigated whether combination with clinically applicable apoptotic modulators (SMAC/BH3 mimetics) can potentiate OV-induced cytokine-mediated killing.
    RESULTS: We confirmed that OVs stimulate PBMCs to produce inflammatory cytokines, which can induce AML cell death. Bystander cytokine-mediated killing was also significantly enhanced in combination with SMAC/BH3 mimetics, with the optimal combination partner varying with AML subtype. We identified interferon (IFN)-α and tumour necrosis factor (TNF)-α as potential mediators of AML cytotoxicity, and SMAC/BH3 mimetics enhanced AML cell death following direct OV infection, indicating autocrine-paracrine signalling events. Pivotally, we confirmed that apoptotic modulators were effective in combination with both Live- and UV-inactivated virus.
    CONCLUSION: This work has identified a novel reovirus-based combination-immunotherapy for the treatment of AML.
    DOI:  https://doi.org/10.1038/s41416-026-03417-x
  18. bioRxiv. 2026 Mar 13. pii: 2026.03.10.710924. [Epub ahead of print]
    Combined Menin and XPO1 inhibition drive synergistic antileukemic activity in KMT2A r and NPM1 -m AML.
    Md Hafiz Uddin, Sandhya Dhiman, Yufen Han, Amro Aboukameel, Vikram Dhillon, Jeff Aguillar, Steven Buck, Abhinav Deol, Julie L Boerner, Lisa Polin, Linda Kessler, Francis Burrows, Jay Yang, Asfar S Azmi, Jaroslaw P Maciejewski, Jevon Cutler, Yang Du, Suresh Kumar Balasubramanian.
      Menin scaffolds the oncogenic histone-lysine-N-methyltransferase (KMT2A)-fusion protein (FP) complex in KMT2A- r and wild-type KMT2A complex in NPM1 -m acute myeloid leukemia (AML). Menin inhibitors (MIs) are effective in KMT2A -r AML and NPM1 -m AML. However, not all patients respond to MIs as monotherapy. In this preclinical study, we demonstrate that the MI ziftomenib, in combination with the XPO1 inhibitor selinexor, synergistically inhibited the growth of multiple KMT2A- r and NPM1 -m AML cell lines (CI<1). The combination suppressed colony formation in primary CD34+ KMT2A- r progenitor cells without affecting normal stem cells. Robust apoptosis and decreased G2/M populations were also evident. The combination downregulated HOXA9 and MEIS1 while upregulating monocytic differentiation marker CD11b in both the AML molecular signatures. RNA sequencing and proteomic analysis in KMT2A- r revealed suppression of multiple bona fide menin-KMT2A target genes. Our mechanistic studies also identified a novel role of XPO1 in stabilizing menin's binding to chromatin and its interactions with KMT2A and KMT2A/MLLT3. XPO1 inhibitor-mediated disruption of these interactions, particularly in combination with ziftomenib, synergistically impairs oncogenic transcriptional programs. In vivo , combination therapy improved survival in both MV4;11 and OCI-AML3 cell line and primary patient-derived KMT2A - r and NPM1 -m AML xenograft models in NSG mice, effective even at reduced drug doses. These preclinical findings demonstrate that simultaneous inhibition of the menin-KMT2A interaction and XPO1 can be a more effective translational strategy for treating KMT2A- r and NPM1 -m AML than MI monotherapy to deepen responses and delay/prevent relapses.
    DOI:  https://doi.org/10.64898/2026.03.10.710924
  19. Blood Cancer J. 2026 Apr 07. pii: 55. [Epub ahead of print]16(1):
    Association between treatment-emergent cytopenias and clinical responses to imetelstat in lower-risk myelodysplastic syndromes.
    Amer M Zeidan, Valeria Santini, María Díez-Campelo, Michael R Savona, Mikkael A Sekeres, Yazan F Madanat, Pierre Fenaux, Azra Raza, Moshe Mittelman, Sylvain Thépot, Rena Buckstein, Ulrich Germing, David Valcárcel, Anna Jonášová, Sheetal Shah, Qi Xia, Libo Sun, Shyamala Navada, Tymara Berry, Uwe Platzbecker, Rami S Komrokji.
      
    DOI:  https://doi.org/10.1038/s41408-026-01501-2
  20. Blood Adv. 2026 Apr 07. pii: bloodadvances.2025018830. [Epub ahead of print]
    DLK1 is a GATA1s-Driven Dependency and Therapeutic Target in Down Syndrome-Associated Myeloid Leukemia.
    Lonneke Verboon, Sonali P Barwe, Meredith Tavenner, Joshua R Faust, Hasan Issa, José Goncalves-Dias, Konstantin Schuschel, Raj Bhayadia, Patrick H van Berkel, Aimy Sebastian, Rhonda E Ries, Sophie Paczesny, Soheil Meshinchi, Johann K Hitzler, Yana Pikman, E Anders Kolb, Dirk Heckl, Jan-Henning Klusmann, Anilkumar Gopalakrishnapillai.
      Children with Down syndrome have a markedly increased risk of developing myeloid leukemia (ML-DS). Although having an excellent prognosis, 10-20% develop relapsed or refractory disease with poor survival, highlighting the need for new targeted approaches. The pathogenesis of ML-DS is tightly linked to fetal hematopoiesis and mutations in GATA1, generating the truncated GATA1short(s) isoform. We identified Delta-like non-canonical Notch ligand 1 (DLK1) as a direct GATA1s target. DLK1, a paternally imprinted transmembrane protein, is highly expressed in fetal liver CD34⁺ cells but absent in adult hematopoiesis, making it an attractive immunotherapeutic target. Chromatin profiling revealed GATA1s occupancy at a distal enhancer within the DLK1-DIO3 locus, driving aberrant DLK1 upregulation in ML-DS. Functional studies demonstrated that DLK1 is a leukemia dependency, as its genetic ablation impaired proliferation and engraftment, induced apoptosis, and altered Notch and β-catenin signaling. Therapeutically, a DLK1-directed antibody-drug conjugate (DLK1-ADC) induced selective cytotoxicity, abrogated colony formation, and significantly prolonged survival in refractory ML-DS PDX models, achieving durable remissions at higher doses. These findings establish DLK1 as a leukemia-specific vulnerability and provide preclinical proof-of-concept for DLK1-targeted therapies in ML-DS and other leukemias with fetal-like expression programs.
    DOI:  https://doi.org/10.1182/bloodadvances.2025018830
  21. Blood. 2026 Mar 19. pii: blood.2025030424. [Epub ahead of print]
    MYB activity drives emergent enhancer activation and enhancer-promoter interactions in acute lymphoblastic leukemia.
    I-Jun Lau, Gianna Bloye, Alastair L Smith, Joe Harman, Joseph C Hamley, Vassilena Sharlandjieva, Nicholas David Robert Denny, Catherine Chahrour, Hangpeng Li, Nicole Jackson, Paresh Vyas, James Davies, Jim R Hughes, Nicholas Crump, Thomas A Milne.
      Aberrant enhancer usage is a defining feature of oncogenic transcriptional reprogramming. Therapeutic strategies that disrupt enhancer-driven gene regulation may offer new treatment avenues. MYB is a key hematopoietic transcription factor that is frequently dysregulated in a broad range of cancers and plays a critical role in sustaining malignant cell states, including in aggressive leukemia subtypes such as KMT2A-rearranged (KMT2A-r) leukemias. The molecular mechanisms by which it maintains oncogenic transcription remain incompletely understood. Here, we investigate the role of MYB in directing pathological enhancer activity to drive oncogene expression in leukemia. Using high-resolution Micro-Capture-C, we show that upon MYB degradation, highly defined enhancer-promoter interactions at MYB binding sites are lost, correlating with significant downregulation of target gene expression. When anchored to a gene desert region, the Myb transactivation domain (MybTA) is sufficient and necessary for nucleation of an enhancer-like region. Critically, long-range chromatin interactions are established up to 400 kb away from where MybTA is anchored. This results in the activation of transcription from distal cryptic elements, which is reduced or abolished in the presence of point mutations that disrupt its interaction with the co-activators P300/CBP. Together, these results indicate that MYB activity alone is sufficient to generate an enhancer, inducing transcription through precise enhancer-promoter crosstalk, and identify the MYB-P300/CBP axis as a therapeutically actionable vulnerability in enhancer-driven malignancies.
    DOI:  https://doi.org/10.1182/blood.2025030424
  22. Cancer Res. 2026 Apr 09.
    Nonsense-Mediated RNA Decay is a Targetable Vulnerability in Splicing Factor Mutant Myeloid Neoplasms by Enhancing R-loop Accumulation and DNA Damage.
    Claudia Cabrera Pastrana, Sridhar Nonavinkere Srivatsan, Michael O Alberti, Tareq Hossan, Tanzir Ahmed, Jin Shao, Monique Chavez, Sarah Grieb, Julia I Padro, Dhanya M Paul, Daniel R George, Ashwini Patil, Sumit Rai, Timothy A Graubert, Julie M Bailis, Zhongsheng You, Matthew J Walter.
      Mutant spliceosome proteins (e.g., U2AF1S34F, SF3B1K700E, or SRSF2P95H) alter RNA splicing in myeloid neoplasms, leading to increased production of nonsense transcripts. Inhibiting the nonsense-mediated RNA decay (NMD) pathway, which is responsible for degradation of nonsense transcripts, preferentially kills cells expressing mutant spliceosome proteins in vitro. In this study, we used an inhibitor of the kinase SMG1, a key regulator of NMD, to provide in vivo evidence that NMD is a therapeutic vulnerability for splicing factor mutant myeloid neoplasms. Primary mouse acute myeloid leukemia cells and human K562 leukemia cell lines expressing splicing factor mutants were more sensitive than wild-type cells to in vivo inhibition of SMG1 (SMG1i). Disruption of NMD activity by SMG1i led to increased R-loop levels in spliceosome wild-type cells, which were further increased in treated U2AF1S34F cells. This R-loop accumulation was accompanied by an increase in DNA damage. Degradation of R-loops with RNase H1 rescued spliceosome mutant cells from NMD inhibition-induced cell death. In U2AF1S34F cells, SMG1i increased NMD transcript isoforms (with reduced but detectable protein levels), which were enriched for DNA repair genes, including ATR and RAD51. Consequently, SMG1i-induced cell death in splicing factor mutant leukemias could be further enhanced by inhibition of ATR or RAD51. This study shows that in vivo targeting of NMD is a therapeutic strategy to treat myeloid neoplasms with aberrant splicing.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-1988
  23. Am J Clin Pathol. 2026 Apr 03. pii: aqag019. [Epub ahead of print]165(4):
    Myeloid/lymphoid precursor cell neoplasms and mixed phenotype acute leukemias: A Bone Marrow Workshop Report from the 22nd European Association for Hematopathology/Society of Hematopathology Meeting, Dubrovnik, 2024.
    Leonie Saft, Alexandar Tzankov, Alexandra Traverse-Glehen, Anna Green, Roos Leguit, Olga Weinberg.
       OBJECTIVES: The bone marrow workshop (session 3), held at the 22nd Meeting of the European Association for Hematopathology/Society of Hematopathology in Dubrovnik, was dedicated to myeloid/lymphoid precursor cell neoplasms and mixed-phenotype acute leukemias (MPALs). We hereby report the clinicopathologic, immunophenotypic, and genetic features of the submitted cases.
    METHODS: The workshop report includes 55 cases; 37 cases represented acute myeloid leukemia (AML) and acute leukemia of ambiguous lineage. Other cases included blast phase of chronic myeloid leukemia (CML), myeloid/lymphoid neoplasms with TK gene fusions (M/LN-TK), and myelodysplastic syndrome (MDS). Additionally, cases of early T-precursor lymphoblastic leukemia (ETP-ALL) and B-precursor lymphoblastic leukemia (B-ALL) were reviewed.
    RESULTS: Among acute leukemia cases, 4 of 8 with the undifferentiated phenotype were reclassified as AML, myelodysplasia related (AML-MR) due to the presence of MDS-related gene mutations or complex karyotype. Thirteen of 20 MPAL cases were reclassified as AML-MR and/or AML with mutated TP53 (fifth edition of the World Health Organization classification/International Consensus Classification). Two cases had complex karyotypes and TP53 mutations, manifesting in the postcytotoxic treatment setting. TP53 mutations were absent in immunophenotypically defined MPAL and in MPAL with BCR::ABL1. Mixed phenotypes were also described in the blast phase of M/LN-TK, CML, and MDS.
    CONCLUSIONS: Mixed phenotype is frequently identified in AML-MR. Future studies are needed to clarify how cases with MR gene mutations and TP53 mutations should be best classified. Additionally, MPAL, T/myeloid, and ETP-ALL and some genetically defined MPAL, B/myeloid, and B-ALL show phenotypic/genetic overlap and are challenging to diagnose. A genomic classification framework is proposed to separate AML-MR and precursor lymphoid neoplasms from MPAL.
    Keywords:  acute leukemia of ambiguous lineage; acute myeloid leukemia; flow cytometry; mixed-phenotype acute leukemia; myelodysplasia-related cytogenetic abnormalities; myelodysplasia-related gene mutations; precursor lymphoid neoplasms
    DOI:  https://doi.org/10.1093/ajcp/aqag019
  24. Haematologica. 2026 Apr 09.
    Disease course of FLT3 mutated extramedullary acute myeloid leukemia and efficacy of gilteritinib.
    Francesco Angotzi, Erika Borlenghi, Chiara Sartor, Maria Benedetta Giannini, Giovanni Marconi, Edoardo Tamellini, Mauro Turrini, Federica Loscocco, Ernesta Audisio, Vincenzo Federico, Calogero Vetro, Francesco Grimaldi, Andrea Visentin, Felicetto Ferrara, Livio Trentin, Carmela Gurrieri, Federica Lessi.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2026.300540
  25. Nat Commun. 2026 Apr 08.
    RPS19 and RPL5 haploinsufficient models reveal divergent ribosomal subunit controls of fetal hematopoiesis.
    Yuefeng Tang, Te Ling, Rashid Mehmood, Alexis Bertrand, Julien Papoin, Mushran Khan, Riaz Rao, Jianing Xu, Vincent Schulz, James Palis, Laurie A Steiner, Betsy J Barnes, Yong-Rui Zou, Philippe Marambaud, Robert A J Signer, Irene Roberts, Deena Iskander, Leonard I Zon, Senthil Velan Bhoopalan, Mitchell J Weiss, Jeffrey M Lipton, Patrick G Gallagher, Narla Mohandas, Naomi Taylor, Sébastien Durand, John Crispino, Lionel Blanc.
      Diamond Blackfan anemia syndrome (DBAS) is a congenital ribosomopathy caused by haploinsufficiency of ribosomal proteins (RPs), but how RP stoichiometry and activity regulates erythroid development remains enigmatic. Using in vivo models, we uncover divergent functions for the small and large ribosomal subunit proteins RPS19 and RPL5 in fetal hematopoiesis. While RPL5 haploinsufficiency causes hematopoietic stem and progenitor cell (HSPC) accumulation and prenatal lethality via p53-mediated ferroptosis of mature erythroid progenitors, RPS19 haploinsufficiency leads to HSPC depletion and impaired erythroid expansion through p53-dependent apoptosis. The latter is accompanied by translational and transcriptional dysregulation, including the upregulation of RUNX1, which is also observed in RPS- haploinsufficient DBAS patients. Importantly, Runx1 deletion in RPS19-haploinsufficient mice partially rescues HSPC numbers. These findings reveal subunit-specific RP functions in controlling fetal hematopoiesis and demonstrate how imbalanced RP stoichiometry disrupts developmental programs, providing crucial mechanistic insights into DBAS pathogenesis and the basis for its clinical heterogeneity.
    DOI:  https://doi.org/10.1038/s41467-026-71727-y
  26. Hemasphere. 2026 Mar;10(3): e70325
    Response to therapy and prognosis according to molecular characterization in CALR-mutated essential thrombocythemia.
    Marta Santaliestra, Marta Garrote, María Concepción Fernández-Rodríguez, Patricia Vélez, Alicia Senín, Eduardo Arellano-Rodrigo, Neus Garcia-Gisbert, Raquel Longarón, Manuel Pérez-Encinas, Gonzalo Caballero-Navarro, Maria Soledad Noya-Pereira, Beatriz Cuevas, María Teresa Gómez-Casares, Ruth Stuckey, Gonzalo Carreño-Tarragona, Francisca Ferrer-Marin, Miguel Angel Cortés, Elena Magro, Isabel Mata, Anna Angona, Raúl Pérez, María Laura Fox, Irene Pastor-Galán, Paula Sastre, Ana Triguero, Valentín García-Gutierrez, Juan Carlos Hernández-Boluda, Beatriz Bellosillo, Alberto Alvarez-Larran.
      Response to cytoreductive therapy according to CALR mutation type, CALR variant allele frequency (VAF), and additional mutations has not been previously studied in essential thrombocythemia (ET). The impact of the molecular profile on treatment response and the main clinical outcomes was analyzed in 557 CALR ET patients (CALR Type 1, n = 339, median VAF 36%; and CALR Type 2, n = 218, median VAF 35%). NGS data on additional mutations were available for 257 patients. CALR Type 2 showed a significantly higher rate of complete hematological response (CHR) to first-line cytoreduction. However, in the multivariate analysis, the effect of CALR mutation type in response rates was no longer significant once CALR VAF was considered, whereas high VAF remained independently associated with a lower likelihood of achieving CHR (hazard ratio [HR] = 0.482, 95% confidence interval (CI): 0.297-0.781; P = 0.003). Moreover, high VAF was also associated with an increased risk of arterial thrombosis (HR = 4.135, 95% CI: 1.093-15.645; P = 0.037), and progression to MF (HR = 2.631, 95% CI: 1.004-6.890; P = 0.049). Although allele burden affects overall survival (OS) in the entire population, its impact was surpassed by the presence of high molecular risk (HMR) mutations (HR = 2.114, 95% CI: 1.070-4.176; P = 0.031). Furthermore, the HMR profile was also associated with a higher risk of progression to acute leukemia, while it did not influence the probability of CHR or progression to MF. In conclusion, CALR VAF and HMR profile appear to be more important than CALR mutation type regarding treatment response and major clinical outcomes in ET.
    DOI:  https://doi.org/10.1002/hem3.70325
  27. Leukemia. 2026 Apr 08.
    A paradigm shift in the treatment of patients with polycythemia vera. The initial early use of recombinant interferon-alpha.
    Richard T Silver, Hans Carl Hasselbalch.
      During the past 35 years, single-arm studies documented the efficacy and safety of recombinant interferon alpha (rIFNα) for treating polycythemia vera (PV). In some patients, 2-5 years of disease-modifying treatment resulted in symptom relief, regression of splenomegaly, normalization of abnormal blood counts and marrow morphology, and sustained JAK2V617F molecular remission. The PROUD-CONTI study showed the superiority of rIFNα compared to hydroxyurea (HU), which led to the European Medicines Agency approval in 2019 of ropeginterferon alpha-2b ("ropegIFN") for ELN-defined high-risk PV patients. In 2021, the Food and Drug Administration (USA) gave unrestricted approval, except for pregnant PV patients. The Low-PV randomized trial established the superiority of ropegIFN compared to phlebotomy-only (PHLEB-O) in ELN-defined low-risk patients. Nevertheless, worldwide, HU remains the cytoreductive drug most often used; maintenance PHLEB-O is still endorsed as maintenance therapy by some hematologists. The National Comprehensive Cancer Network (NCCN, USA) approved ropegIFN as a II-A recommendation for ELN-defined low and high-risk disease; the ELN suggested criteria for using rIFNα in low-risk patients if certain issues developed after PHLEB-O, including more symptoms, progressive splenomegaly, significant leukocytosis, thrombocytosis, or inadequate hematocrit control. These issues are important because even low-risk patients are at increased thrombotic risk, estimated at 2 to 3 times that of the general population. Moreover, as PV progresses, the development of myelofibrosis is the leading cause of morbidity, perhaps abetted by PHLEB-O. Here, we review recent progress in the treatment of PV with rIFNα and discuss our rationales and perspectives for, and the endorsement of the initial treatment with rIFNα of both low and high-risk PV patients, unless a contraindication exists to its use.
    DOI:  https://doi.org/10.1038/s41375-026-02882-w
  28. Nat Commun. 2026 Apr 06. pii: 2798. [Epub ahead of print]17(1):
    Non-necroptotic MLKL function damages mitochondria and promotes hematopoietic stem cell aging.
    Yuta Yamada, Jinjing Yang, Akiho Saiki-Tsuchiya, Yuji Watanabe, Shuhei Koide, Shin Murai, Yuriko Sorimachi, Yu Fukuda, Kenta Sumiyama, Hiroshi Sagara, Hiroyasu Nakano, Keiyo Takubo, Atsushi Iwama, Masayuki Yamashita.
      Hematopoietic stem cells (HSCs) survive many types of cellular stress but often lose their regenerative and lymphopoietic capacities as a result. Such functional decline also occurs with age, and dysfunctional HSCs with impaired mitochondria accumulate during aging. However, the molecular link between HSC stress response and age-related functional decline remains poorly understood. Here we show that multiple stress responses converge on the RIPK3-MLKL axis to induce age-related changes in HSCs. The necroptosis effector MLKL is readily activated by inflammation and replication stress and accumulates in HSC mitochondria. Consequently, activated MLKL does not cause cell death but impairs HSC self-renewal and lymphoid differentiation. Such MLKL-mediated functional decline also occurs in HSCs during organismal aging, with activated MLKL primarily mediating age-related mitochondrial damage and reduced glycolytic flux. Collectively, our results establish the RIPK3-MLKL axis as a key mediator of HSC aging and identify a necroptosis-independent role of MLKL in mitochondrial damage.
    DOI:  https://doi.org/10.1038/s41467-026-71060-4
  29. J Clin Oncol. 2026 Apr 06. JCO2501966
    First-in-Human Study of IL15-Activated Cytokine-Induced Killer Cells After Allogeneic HCT Shows Durable Remission and Serotherapy-Associated Immune Reconstitution in Leukemia.
    Eva Rettinger, Dirk Heckl, Martin Hutter, Emilia Salzmann-Manrique, Marie Luedtke, Sabine Huenecke, Melanie Bremm, Claudia Cappel, Gesine Bug, Johann Greil, Roland Meisel, Eva Maria Wagner-Drouet, Hubert Serve, Tayfun Güngör, Jan-Henning Klusmann, Thomas Klingebiel, Peter Bader, Halvard Bonig.
       PURPOSE: Patients with high-risk (HR) leukemia remain at substantial risk of early relapse, treatment-related toxicity, and poor survival, underscoring the need for effective relapse prevention therapies. To our knowledge, this first-in-human, disease burden-guided study evaluated the feasibility, safety, and efficacy of donor-derived allogeneic interleukin-15-activated cytokine-induced killer cells (IL15-CIK) combining T-cell and natural killer cell properties for post-transplant disease control.
    METHODS: In a prospective, multicenter phase I/II trial (EudraCT 2013-005446-11) and an identically designed pilot study, 53 adult and pediatric patients with HR leukemia received 56 courses of IL15-CIK monotherapy after human leukocyte antigen (HLA)-matched or HLA-mismatched transplantation. Treatment intent was categorized as consolidation (13%), preemptive (61%), or salvage (27%) with 169 infusions administered as a single dose (29%) or according to adaptable dose-escalation regimens (71%).
    RESULTS: Acute graft-versus-host disease (GVHD) grades 1-2 and grade 3 occurred in 27% and 4% of cases, respectively; no extensive chronic GVHD or treatment-related mortality was observed. IL15-CIK-associated adverse events were predominantly mild. Disease clearance, assessed by the cumulative incidence of complete molecular remission, peaked at day 700, reaching 74% in the preemptive and 13% in the salvage setting. The five-year progression-free survival was 50% overall and highest (69%) in pediatric acute myeloid leukemia. The five-year overall survival (OS) was 71% in the consolidation, 61% in the preemptive, and 20% in the salvage setting. Multivariable analysis demonstrated significantly lower relapse rates with Campath compared with ATG, superior OS in myeloid malignancies, and reduced IL15-CIK efficacy in advanced disease. The median follow-up was 7.3 years.
    CONCLUSION: IL15-CIK monotherapy is feasible and safe and demonstrates promising relapse-preventive activity after hematopoietic stem-cell transplantation. Clinical outcomes are strongly influenced by disease burden at treatment initiation and previous serotherapy, supporting optimized patient selection and timing in future post-transplant immunotherapeutic strategies.
    DOI:  https://doi.org/10.1200/JCO-25-01966
  30. bioRxiv. 2026 Mar 30. pii: 2026.03.26.714544. [Epub ahead of print]
    Glutamine addiction is a therapeutic target to block emergency myelopoiesis.
    Oakley C Olson, Ruiyuan Zhang, Melissa A Proven, James C Swann, Kexuan Huang, William E Lowry, Emmanuelle Passegue.
      Inflammation-driven emergency myelopoiesis (EM) contributes to the progression of many solid cancers and inflammatory diseases, yet therapeutic strategies to selectively suppress EM without compromising hematopoiesis remain lacking. Here, we use functional and single-cell transcriptomic analyses to determine metabolic programs organizing the hematopoietic hierarchy, myeloid lineage commitment, and myeloid differentiation. We identify de novo glutamine biosynthesis as a stem cell-specific survival mechanism allowing independence from exogenous glutamine. We show that myeloid differentiation is characterized by Myc-driven upregulation of mitochondrial respiration, which is hyperactivated during EM and renders myeloid progenitors dependent on glutaminolysis to fuel the TCA cycle. Both genetic and pharmacologic targeting of glutaminase suppresses EM and impairs breast tumor progression by reducing intratumoral neutrophil infiltration. Our study defines a central role for Myc-glutaminolysis in driving EM, identifies glutaminolysis as a therapeutic target to normalize maladaptive EM, and highlights myeloid overproduction as a systemic problem requiring HSPC targeting.
    DOI:  https://doi.org/10.64898/2026.03.26.714544
  31. Nat Commun. 2026 Apr 06.
    Quizartinib and omacetaxine mepesuccinate combination therapy in FLT3-ITD AML: a phase II trial.
    Li-Chuan Zheng, Kelvin K W Wong, Stephen S Y Lam, Garret M K Leung, Chenqinyao Li, Kwui-Wa Tong, Wing Lam, Xiao-Yuan Zeng, Koon-Chuen Chan, Natalie Nok-Man Chan, Ka-Lam Ng, Chee-Chean Dang, Tsz-Ho Kwok, Sze-Pui Tsui, Rakesh Sharma, Jason W H Wong, Suet-Yi Leung, Anskar Y H Leung, Cheuk-Him Man.
      FLT3-ITD inhibitors are approved for acute myeloid leukemia (AML) treatment but relapse is common. In this study, the combined inhibition of FLT3-ITD signal and protein translation by QUIZartinib and Omacetaxine Mepesuccinate (QUIZOM) synergistically suppressed the most critical FLT3-ITD survival signals including mitochondrial respiration and proteostasis, which induced apoptosis and pro-inflammatory response. In a Phase 2 trial (NCT03135054) involving 40 chemo-refractory/unfit FLT3-ITD AML patients, QUIZOM achieved a composite complete remission (CRc) of 83%, a median leukemia-free survival (LFS) of 10 months (Range: 0.7-68.2 months) and a median overall survival (OS) of 12.9 months (Range: 1.8-69.2 months). 13/33 (39%) received allogeneic HSCT after a median of 143 days (Range: 53-367 days). Higher CRc rates were observed in patients with NPM1 mutations, DNMT3A mutations, and wild-type WT1. Single-cell RNA-sequencing of QUIZOM cohort revealed positive correlation between pro-inflammatory response in blasts, CD8 + T activation and clinical responsiveness. Further, we identified a leukemic stem cell (LSC) subpopulation with activated JNK/JUN/HSPA1B axis via PLD1-driven phosphatidylcholine metabolism, which promoted proteostasis and drove QUIZOM resistance. PLD1-inhibitor remodeled phospholipid metabolism, induced ferroptosis and restored QUIZOM response in LSC. Our findings provided the therapeutic and resistant mechanisms of QUIZOM and paved the way for targeted interventions in this AML subtype.
    DOI:  https://doi.org/10.1038/s41467-026-71186-5
  32. Blood. 2026 Apr 06. pii: blood.2025032031. [Epub ahead of print]
    The ASH HematOmics Program supports integrative analysis of genomic and clinical data in hematologic diseases.
    Congyu Lu, Gavriel Y Matt, Robin Paul, Jian Wang, Edgar Sioson, Karishma Gangwani, Aleksandar Acić, Andrew Willems, Airen Zaldívar Peraza, Colleen Reilly, Petri Pölönen, Qingsong Gao, Qian Li, Stanley B Pounds, Andy G X Zeng, Sihan Li, Niroshan Nadarajah, Samuel W Brady, Ilaria Iacobucci, Torsten Haferlach, Miquella C Rose, Charles G Mullighan, Xin Zhou.
      The increasing availability of genomic and transcriptomic sequencing has uncovered diverse genomic alterations and distinct gene expression profiles driving hematologic diseases, yet a data integration and sharing platform dedicated to hematology remains lacking. We developed the American Society of Hematology (ASH) HematOmics Program (ASHOP, ashop.hematology.org), a resource for exploring somatic alterations and gene fusions, transcriptomic results, and clinical data from 5,960 patients spanning B-cell precursor and T-cell acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndromes, and chronic lymphocytic leukemia. Users can explore genomic alteration landscapes and co-mutation patterns via lollipop and matrix plots, and analyze significantly altered genes in user-defined sub-cohorts. Transcriptomes can be explored through interactive UMAPs, clustering, differential expression, and pathway enrichment. Genomic, transcriptomic features, and clinical outcomes can be correlated in a user-driven manner, or combined to precisely define study cohorts. We illustrate four use cases of ASHOP: (1) stratification of DUX4-rearranged B-cell leukemias into Early/Multipotent and Committed subgroups with distinct outcomes, (2) characterization of HOXA/HOXB expression patterns in acute myeloid leukemias, (3) correlating mutational burden with mismatch repair deficiency and mutational signatures, (4) investigation of TP53 alteration landscape. ASHOP is an open-access resource to inform genomic and transcriptomic data interpretation for hematologic malignancies, and will expand to support additional diseases and data modalities from the ASH community.
    DOI:  https://doi.org/10.1182/blood.2025032031
  33. Blood Adv. 2026 Apr 09. pii: bloodadvances.2026020278. [Epub ahead of print]
    Eligibility is not appropriateness: Reframing the role of age in allogeneic transplant decision-making.
    Mohamed L Sorror, Andrew S Artz, Rebecca L Olin, Reshma Ramlal, Sergio A Giralt.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2026020278
  34. bioRxiv. 2026 Apr 01. pii: 2026.03.30.715412. [Epub ahead of print]
    Stem cell function in vivo is supported by an alternative glycolysis endpoint.
    Edward O Kwarteng, Yafeng Li, Dieu Linh Nguyen, Michalis Agathocleous.
      Carbohydrates are classically catabolized by fermentation or oxidation, a choice that impacts many cellular functions including proliferation. Proliferating cells including somatic stem and progenitor cells are thought to favor fermentation over oxidation, and most proliferating cells in vitro depend on lactate production. However, it has not been tested if fermentation and oxidation are the universal obligatory terminal fates for carbohydrates in vivo because the key enzymes, lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH), have not been simultaneously deleted in any cell type. Here we show that both fermentation and oxidation are dispensable for the survival and function of hematopoietic stem cells (HSC). Combined LDHA and LDHB deletion to ablate LDH did not impair HSC function, suggesting that HSCs and rapidly proliferating hematopoietic progenitors surprisingly do not require fermentation. Combined LDHA, LDHB, and PDH deletion abolished both glucose oxidation and fermentation, but did not impair HSC function. Glycolysis was preserved, suggesting the operation of an alternative endpoint. LDH/PDH-deficient HSCs terminated glycolysis through pyruvate export. Pyruvate export by HSCs and progenitors was a physiological response to changing nutrient levels. Quadruple deletion of LDHA/B, PDH, and the pyruvate transporter MCT1 impaired HSC function. This suggested that an essential role of glycolysis termination is not to produce acetyl-CoA or lactate but to remove pyruvate. Therefore, in contrast to classical theories and to in vitro metabolism, carbohydrate metabolism in vivo does not require oxidation or fermentation but can terminate directly in pyruvate export, and this alternative pathway is sufficient to support stem cell function.
    DOI:  https://doi.org/10.64898/2026.03.30.715412
  35. Hemasphere. 2026 Apr;10(4): e70349
    Erdheim-Chester disease associated with myeloid neoplasm: Clinical features, molecular landscape, and treatment outcomes.
    Ambroise Le Pogam, Matthias Papo, Pierre Hirsch, Fleur Cohen-Aubart, Jean-François Emile, François Delhommeau, Pierre Duffau, Jérôme Razanamahery, Florence Nguyen-Khac, Christopher Nunes Gomes, Felicien Triboulet, Jeanne de La Rochefoucauld, Chloé McAvoy, Estibaliz Lazaro, Mehdi Hage-Sleiman, Damien Roos-Weil, François Chasset, Vincent Jachiet, Arsène Mekinian, Olivier Fain, Zahir Amoura, Jérôme Hadjadj, Julien Haroche.
      Erdheim-Chester disease (ECD) is frequently associated with clonal hematopoiesis and myeloid neoplasms (MN), but clinical phenotype and response to kinase inhibitors (KI) in this setting remain unclear. We analyzed 67 patients with ECD associated with MN (ECD-MN) from a French national cohort and assessed ECD treatment response, MN progression, and leukemic transformation. Outcomes were compared with those of 348 patients with ECD without MN. ECD-MN were characterized by low blast counts and favorable MN prognostic scores. Compared with ECD patients without MN, those with MN were older (median 65 vs. 59 years, P < 0.0001) and had more frequent cardiac (54% vs. 37%, P < 0.01), pulmonary (48% vs. 31%, P < 0.01), gastrointestinal (34% vs. 11%, P < 0.0001), and lymph node involvement (31% vs. 8%, P < 0.0001). KI therapy led to higher ECD response rates at 6 and 12 months compared with pegylated-interferon α (Peg-IFN) (96% vs. 58%, P = 0.02). MN progression and leukemic transformation at 6 months occurred, respectively, in 25% and 3% of KI-treated patients versus 25% and 18% of those treated with Peg-IFN. After a median follow-up of 25 (12-38) months on KI, the mutational landscape remained unchanged. Median overall survival was shorter in patients with MN (76 vs. 163 months, P < 0.001). In conclusion, ECD associated with MN represents a distinct clinical entity, marked by broader organ involvement and poorer prognosis. KI therapy provides a superior response without increasing the risk of MN progression or leukemic transformation, supporting its use as a frontline treatment in this population.
    DOI:  https://doi.org/10.1002/hem3.70349
  36. Lancet Haematol. 2026 Apr;pii: S2352-3026(26)00031-1. [Epub ahead of print]13(4): e197-e198
    Concomitant or sequential lower intensity triplet therapy in AML.
    Jayastu Senapati, Naval G Daver, Jayanshu Jain, Alice S Mims.
      
    DOI:  https://doi.org/10.1016/S2352-3026(26)00031-1
  37. iScience. 2026 Apr 17. 29(4): 115337
    A multimodal atlas for immunotherapeutic targeting of AML surface heterogeneity.
    Matthew Ung, Julia Etchin, Amanda Halfond, Julia DiFazio, Yonina Keschner, Alyssa Pyclik, Anne Campbell, Ruijia Wang, Mariana Silva, Brikena Gjeci, Antonino Montalbano, Reid Williams, Guy Mundelboim, Andrea Arruda, Mark Minden, Julian Scherer, Tirtha Chakraborty, Huanying Gary Ge, John R Lydeard.
      Acute myeloid leukemia (AML) is a hematologic malignancy with high relapse rates and limited treatment options due to extensive intra-tumor heterogeneity across patients. To characterize this heterogeneity, we profiled matched bone marrow mononuclear cell (BMMC) samples from 26 patients with adult AML at diagnosis and relapse using the cellular indexing of transcriptome and epitope sequencing (CITE-seq) and quantitative flow cytometry. These data together represent a comprehensive multimodal and longitudinal single-cell resource that reveals the transcriptomic and immunophenotypic landscape of AML. Data integration of CITE-seq and flow cytometry surface antigen readouts enabled systematic quantitation of surface antigen co-expression across individual leukemic cells, providing a granular framework for the design of immunotherapeutic strategies to target heterogeneous AML. With this resource, we identified CD33, CLL-1, LAIR1, ITGA4, DEC-205, and CD244 as antigens that induced cytotoxicity in AML cell lines in vitro when co-targeted by antibody drug conjugates (ADCs) or chimeric antigen receptor T (CAR-T) cells, demonstrating the exploitation of AML heterogeneity for immunotherapeutic innovation.
    Keywords:  Cancer; Immune response; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2026.115337
  38. bioRxiv. 2026 Mar 31. pii: 2026.03.30.714548. [Epub ahead of print]
    5-Azacytidine incorporation into mRNAs disrupts translation and induces ribosome collisions.
    Alexis B Roberson, James Marks, Ruby Pitts, Bavavarshini Tamilselvam, Brian Grieb, William P Tansey, Sezen Meydan.
      5-Azacytidine (5-AzaC) is a cytidine analog and is widely used to treat myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Although its therapeutic activity is primarily attributed to hypomethylation resulting from DNA incorporation, the majority of 5-AzaC is incorporated into RNA. However, the functional consequences of 5-AzaC incorporation into RNA have been unknown. Here, we show that 5-AzaC treatment of cells leads to inhibition of protein synthesis. Ribo-seq, Disome-seq, and RNA-seq in cells treated with 5-AzaC exhibit a time-dependent C-to-G transversion signature in mRNAs within 2 h of treatment. These transversion events are enriched within footprint positions corresponding to the A-site of monosomes or leading stalled ribosome in a disome complex. Consistently, ribosome and disome footprints are accumulated at sites with C-rich codons in the A-site, specifically with the codons containing a C in the second position. 5-AzaC activates the integrated stress response (ISR) and the ribotoxic stress response (RSR) in a GCN2- and ZAK-dependent manner, consistent with disome-mediated signaling. Furthermore, loss of the Ribosome Quality Control (RQC) factor, ZNF598, sensitizes cells to 5-AzaC. Collectively, our results support a model where 5-AzaC is rapidly incorporated into mRNAs, disrupts decoding, and triggers disome-mediated signaling pathways, which contribute to its cytotoxicity. These findings suggest that translation disruption represents an additional layer of 5-AzaC's mechanism of action, alongside its known DNA-mediated effects.
    DOI:  https://doi.org/10.64898/2026.03.30.714548
  39. Blood. 2026 Mar 20. pii: blood.2025031880. [Epub ahead of print]
    Nuclear Transcriptional Condensates as Drivers and Therapeutic Targets in NPM1-mutated AML.
    Hannah Julia Uckelmann, Jayant Yadunath Gadrey, Lorenzo Brunetti.
      NPM1-mutated AML is driven by aberrant HOX/MEIS1 expression, whose mechanistic basis remained unresolved for years. Recent paradigm-shifting studies show that mutant NPM1 organizes phase-separated nuclear condensates that concentrate transcriptional regulators at active chromatin, directly sustaining the pathogenic HOX/MEIS1 transcriptional program. This framework explains the activity of Menin-KMT2A inhibitors, recently approved by the FDA, in this AML subtype and positions disruption of these assemblies as a precision strategy to eliminate oncogenic transcription.
    DOI:  https://doi.org/10.1182/blood.2025031880
  40. Cancer Immunol Immunother. 2026 Apr 11. pii: 143. [Epub ahead of print]75(5):
    A phase I, single-arm, open-label, dose-escalation, multicenter study of SAR445419, an off-the-shelf, ex vivo expanded allogeneic natural killer cell product, in participants with relapsed or refractory acute myeloid leukemia.
    Marina Konopleva, Vijaya Raj Bhatt, Ioannis Mantzaris, Abhishek Maiti, Krishna Gundabolu, Jolie Schafer, Kyle Jensen, Rao Saleem, Yi Li, Agata Drewniak, Pierre Bay, Winston Huh, Ozlem Yildirim, Giovanni Abbadessa, Sarah Cooley, Naval Daver.
       BACKGROUND: SAR445419 is an investigational, off-the-shelf, allogeneic NK cell therapy derived from donor peripheral blood mononuclear cells and expanded ex vivo using PM21 particles.
    METHODS: This multicenter, Phase 1, dose-escalation study (NCT05712278) evaluated optimal dose(s), safety, and tolerability of SAR445419 in adults (aged ≥ 18 years) with relapsed/refractory acute myeloid leukemia (R/R AML). Following lymphodepleting chemotherapy (fludarabine 30 mg/m2/day and cytarabine 2 g/m2/day for 5 days), participants received six intravenous SAR445419 (1 × 109 and 3 × 109 NK cells/dose) doses, starting with the lower dose. The primary endpoint was the incidence of dose-limiting toxicities (DLTs), and key secondary endpoints included adverse events (AEs), hematological recovery, hematopoietic stem cell transplantation, and response rate.
    RESULTS: Of the 12 planned participants, 7 patients were enrolled, of whom 6 received SAR445419 before sponsor decided early study termination for reasons unrelated to safety or efficacy. No DLTs were observed. All participants experienced treatment-emergent adverse events (TEAEs); six had grade ≥ 3 TEAEs; and four had serious adverse events (SAEs). Two SAR445419-related SAEs (infusion-related reactions: both grade 2) were managed with supportive care. All participants experienced grade 3 anemia and grade 4 thrombocytopenia and neutropenia. Five deaths were reported, all due to disease progression, none related to SAR445419. No clinical responses were observed.
    CONCLUSIONS: This study demonstrated the overall safety of off-the-shelf ex vivo expanded allogeneic NK cells in patients with R/R AML. The successful manufacturing and distribution support the feasibility of donor-derived off-the-shelf NK cells in a clinical setting. Further investigations are required to improve the clinical efficiency of NK cells.
    Keywords:  Cellular therapy; NK cell manufacture; NK cells; Phase 1; R/R AML
    DOI:  https://doi.org/10.1007/s00262-026-04333-y
  41. Br J Haematol. 2026 Apr 05.
    Trends in survival outcomes after allogeneic transplantation for MDS and MDS/MPN in a real-world experience: A 25-year nationwide study.
    adult MDS and CML/MPN working groups of the Japanese Society for Transplantation and Cellular Therapy
      Allogeneic haematopoietic stem cell transplantation (allo-HSCT) offers a curative potential for myelodysplastic syndrome (MDS) and myelodysplastic/myeloproliferative neoplasm (MDS/MPN). We examined survival trends using a nationwide database of 7175 patients who underwent their first allo-HSCT between 1998 and 2022. Overall mortality decreased over time in patients with early MDS (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.65-0.97, p = 0.026 in 2013-2017; HR 0.54, 95% CI 0.42-0.70, p < 0.001 in 2018-2022), advanced MDS (HR 0.80, 95% CI 0.71-0.90, p < 0.001 in 2013-2017; HR 0.74, 95% CI 0.65-0.85, p < 0.001 in 2018-2022), chronic myelomonocytic leukaemia (HR 0.45, 95% CI 0.32-0.64, p < 0.001 in 2013-2017; HR 0.53, 95% CI 0.37-0.74, p < 0.001 in 2018-2022) and atypical chronic myeloid leukaemia (HR 0.32, 95% CI 0.13-0.80, p = 0.016 in 2013-2017; HR 0.26, 95% CI 0.10-0.68, p = 0.006 in 2018-2022). These decreases in overall mortality were mainly attributable to reductions in non-relapse mortality. Meanwhile, no significant difference in overall mortality was observed in patients with MDS/MPN-unclassified and therapy-related myeloid neoplasm. Across all disease subtypes, relapse incidence did not significantly decrease over time, highlighting persistent challenges in reducing the risk of post-transplant relapse.
    Keywords:  allogeneic haematopoietic stem cell transplantation; myelodysplastic syndrome; myelodysplastic/myeloproliferative neoplasm; survival outcomes
    DOI:  https://doi.org/10.1111/bjh.70463
  42. Science. 2026 Apr 09. 392(6794): eady5196
    Sialylated CD43 forms a glyco-immune barrier that restrains antileukemic immunity.
    Jooho Chung, Mounica Vallurupalli, Sarah Noel, Gail Schor, Sofia Mrowka, Ilario Scapozza, Zelalem Demere, Sachin V Kammula, Margaret Hu, Sarah Y Kim, YuhJong Liu, Celeste Nobrega, Jonathan J Perera, Ewa Wrona, Collins K Cheruiyot, Yunkang Lin, David W Wu, Maria Saberi, Aidan Cruickshank, Elliot C Woods, Cun Lan Chuong, Filippo Birocchi, Ashwin V Kammula, Omar I Avila, Nelson Knudsen, Mustafa Kocak, John G Doench, Dean Procter, Lindsey Thornton, Andrew M Brunner, Eric Winer, Daniel J DeAngelo, Jacqueline S Garcia, Richard M Stone, Russell W Jenkins, Marcela V Maus, Timothy A Graubert, Kathleen B Yates, Todd R Golub, Robert T Manguso.
      Macrophages exert antitumorigenic activity through phagocytosis, but phagocytosis-enhancing therapeutics have not improved acute myeloid leukemia (AML) outcomes. To identify phagocytosis regulators, we performed CRISPR knockout screens in human AML cells cocultured with human macrophages. We found that the "don't eat me" signal CD47 inhibited mouse but not human macrophage phagocytosis. However, O-linked glycosylation and sialylation were strong negative regulators of phagocytosis. In AML, the cell surface mucin-like glycoprotein CD43 was the major effector of these pathways. Inhibition of phagocytosis by CD43 was dependent on the length of its ectodomain and independent of the macrophage sialic acid receptors SIGLEC-1, SIGLEC-7, and SIGLEC-9. The inhibitory effects of CD43 extended beyond human macrophages to natural killer and T cells. Thus, CD43 forms a glyco-immune barrier that restrains both innate and adaptive antileukemic immunity.
    DOI:  https://doi.org/10.1126/science.ady5196
  43. Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2532472123
    Structure-guided design of 7-azaindole DNMT1 inhibitors active against hypomethylating agent-resistant acute myeloid leukemia.
    Shibing Tang, Liangyi Zong, Shuyuan Ma, Yini Shang, Jiale Wei, Jianguang Liu, Ying Cui, Huahui Guo, Kang Zou, Kezhi Wang, Hongkun Li, Fei Ye, Jing Huang, Cheng Luo, Zhihai Li, Stephen B Baylin, Xiangqian Kong.
      Pharmacological reversal of abnormal promoter DNA hypermethylation at tumor suppressor genes (TSGs) is a key therapeutic paradigm for cancer management. However, the clinical efficacy of currently approved nucleoside analog hypomethylating agents (HMAs) is limited by dose-dependent toxicity and high resistance rates. Nonnucleoside, DNA methyltransferase 1 (DNMT1)-selective inhibitors offer a promising alternative. To date, only limited chemotypes, exemplified by the dicyanopyridine derivative GSK3685032 (GSK5032), have demonstrated translatable DNMT1 inhibition, with resistance emerging upon prolonged exposure. To address these limitations, we employ structure-guided scaffold hopping and chemical optimization to develop a series of DNMT1 inhibitors (DNMT1i) featuring a bicyclic 7-azaindole scaffold. We identify DMI46, a potent enzymatic DNMT1i capable of reversing cancer-specific DNA methylation abnormalities and TSG silencing, leading to robust antileukemic effects and favorable tolerability. Cryoelectron microscopy (cryo-EM) studies reveal that the 7-azaindole inhibitor exhibits enhanced intercalation into hemi-methylated CpG dyads and increased minor-groove contacts within the DNMT1/hemimethylated DNA complex compared to GSK5032. These structural features enable sustained DNMT1 targeting and significant antiproliferative activity of DMI46 in GSK5032-resistant acute myeloid leukemia (AML) cells. We also demonstrate DMI46's capacity to overcome AML resistance to nucleoside-based HMAs both in vitro and in vivo. These findings introduce a distinct DNMT1i chemotype with enhanced on-target engagement and broad applicability against HMA-resistant AML.
    Keywords:  DNA hypomethylating agents; DNMT1 inhibitors; acquired drug resistance; structure-based drug design; tumor suppressor gene silencing
    DOI:  https://doi.org/10.1073/pnas.2532472123
  44. FEBS J. 2026 Apr 10.
    Mitochondrial transfer in acute myeloid leukaemia and multiple myeloma: Mechanisms, consequences and potential therapeutic opportunities.
    Ebubechukwu Nwarunma, Mark T S Williams.
      Haematological malignancies, such as acute myeloid leukaemia (AML) and multiple myeloma (MM), which develop from malignant transformations within the bone marrow, represent the most critical unmet needs in the haemato-oncology field. Sub-optimal clinical outcomes in patients with AML and MM are often driven by resistance to chemotherapy. It is well established that cells within the bone marrow microenvironment (BMME) support the proliferation and survival of these blood cancer cells. One of the mechanisms by which these BMME-resident cells support the malignant cells is through horizontal mitochondrial transfer (HMT), a mechanism well documented as occurring under steady-state conditions as well as in many cancers. Recent research implicates mitochondrial transfer in BMME-driven chemoresistance in AML and MM. In this review, we critically analyse current understanding of the role of HMT in supporting the survival and proliferation of AML and MM cells, as well as driving resistance to cytotoxic effects of chemotherapy. We further elucidate various mechanisms, molecular triggers, functional consequences, and therapeutic implications for HMT in AML and MM. Our review also highlights unanswered questions within the HMT field and provides a theoretical basis for further study, giving direction on what is important in translating this knowledge into effective future therapeutic strategies.
    Keywords:  Horizontal mitochondrial transfer (HMT); Multiple myeloma (MM); acute myeloid leukaemia (AML); bone marrow microenvironment (BMME); chemoresistance
    DOI:  https://doi.org/10.1111/febs.70544
  45. Haematologica. 2026 Apr 09.
    Changes in neutrophil-to-lymphocyte ratio in patients with polycythemia vera treated with ruxolitinib reflect JAK2 variant allele frequency.
    Paola Guglielmelli, Chiara Paoli, Giulia Borgi, Lorenzo Fagiolo, Sara Bianchini, Giuseppe Gaetano Loscocco, Francesca Gesullo, Fernanda Di Vaio, Cecilia Matteoli, Fabiana Pancani, Sofia Danesi, Simona Pestelli, Tiziano Barbui, Alessandro M Vannucchi.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2025.300245
  46. Exp Hematol. 2026 Apr 02. pii: S0301-472X(26)00061-5. [Epub ahead of print] 105428
    The rise of bone marrow organoids as next-generation models for blood formation and failure.
    Anne Stolz, Lauren M Harmon, Jingjing Li, Jasmin Rettkowski, Alba Rodriguez-Meira, Kohei Shiroshita, Vu L Tran, Abdullah Khan, Christoph Klein.
      Bone marrow organoids (BMOs) are three-dimensional cell culture models that recapitulate key structural and functional features of the bone marrow (BM) niche. BMOs offer important advantages in hematopoietic research by modeling key aspects of human hematopoiesis compared to classical in vitro two- and three-dimensional cellular models including bioreactors, BM-on-a-chip platforms, 2D models or BM ossicles by better recreating the three-dimensional architecture, cellular heterogeneity, and spatial organization of the BM microenvironment. They offer a scalable and cost-effective alternative to animal models and reduce the need for animal experiments. Induced pluripotent stem cell (iPSC)-derived BMOs can be generated from a patient's own cells, enabling personalized disease modeling and drug testing and are highly amenable to gene editing technologies allowing precise modifications to study gene function or model diseases. Recent landmark studies from Christoph Klein and Abdullah Khan have established protocols for the generation of BMOs and demonstrated their applications in disease modeling. Here, we review the critical steps in BMO generation, their structural/ functional validation and discuss how BMOs can be applied to model inflammatory responses, rare genetic bone marrow failure syndromes, and multiple myeloma. These advances demonstrate BMOs' growing potential as powerful tools in hematopoietic research and will pave the way for further innovation and increasingly refined systems in future studies.
    Keywords:  bone marrow niche; bone marrow organoid; disease modeling
    DOI:  https://doi.org/10.1016/j.exphem.2026.105428
  47. Clin Cancer Res. 2026 Apr 06.
    Phase 1 Study of KITE-222, an Autologous CLL-1-directed CAR T-cell Therapy in Patients With Relapsed/Refractory Acute Myeloid Leukemia.
    Naval Daver, James S Blachly, Armin Ghobadi, Anjali Advani, Lori Muffly, Sylvain Garciaz, Christian Recher, Bhaskar Kahali, Jennifer Sun, A Scott Jung, Simone Filosto, Daqin Mao, Enrique Granados, David A Sallman.
       PURPOSE: Chimeric antigen receptor (CAR) T-cell therapy has been a breakthrough in many hematological malignancies but success in relapsed/refractory (R/R) acute myeloid leukemia (AML) has been limited due to underwhelming response rates and high on-target/off-tumor toxicity. This Phase 1 dose-escalation trial evaluated the safety and efficacy of KITE-222, an autologous CAR T-cell therapy that recognizes C-type lectin-like molecule 1 (CLL-1) predominantly expressed on myeloid cells but absent on normal hematopoietic stem cells and other tissues.
    METHODS: Patients with R/R AML (≥50 kg) received a single intravenous infusion of 3×107 (Cohort 1), 1×108 (Cohort 2), or 3×108 (Cohort 3) KITE-222 CAR+ T cells. The primary endpoint was incidence of dose-limiting toxicities (DLTs). Key secondary endpoints included overall remission rate, incidence of adverse events (AEs), and pharmacokinetics/pharmacodynamics.
    RESULTS: Twelve patients received KITE-222. One patient in Cohort 3, who was the only patient to receive 2 courses of lymphodepleting chemotherapy, experienced a DLT (prolonged Grade 4 neutropenia/thrombocytopenia) but achieved a best response of morphologic leukemia-free state on Day 14 following infusion (confirmed on Day 44). All patients experienced Grade ≥3 AEs, none had Grade ≥3 cytokine release syndrome, and 1 had Grade ≥3 immune effector cell-associated neurotoxicity syndrome. Clinically meaningful responses were lacking across dose levels despite detectable CAR T-cell expansion. Although 2 of 5 Cohort 3 patients with clear expansion had near complete depletion of CLL-1+ bone marrow blasts after infusion, CLL-1- blasts persisted, and reductions in total blasts were not observed.
    CONCLUSIONS: Despite successful manufacturing and acceptable safety, KITE-222 lacked preliminary efficacy, warranting future studies that address CLL-1 heterogeneity and focus on improving in vivo expansion and antitumor activity.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-3745
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