bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2026–05–10
38 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Combining Menin and MEK inhibition to target poor prognosis KMT2A-rearranged RAS pathway-mutant acute myeloid leukemia.
  2. U2af1S34F and U2af1Q157R myeloid neoplasm-associated hotspot mutations induce distinct hematopoietic phenotypes in mice.
  3. Transposable elements shape stemness in normal and leukemic hematopoiesis.
  4. Genetic variation reveals a homeotic long noncoding RNA that modulates human hematopoietic stem cells.
  5. Single cell long read genotyping of transcripts reveals discrete mechanisms of clonal evolution in post-MPN AML.
  6. How I utilize somatic alterations in the diagnosis, risk stratification, and therapy of hypocellular bone marrow failure.
  7. MECOM promotes leukemia progression and inhibits mast cell differentiation through functional competition with GATA2.
  8. Myelodysplastic syndrome with concomitant SF3B1 mutation and deletion of chromosome 5 long arm: outcomes and response to treatment.
  9. Prognostic impact of ASXL1 mutations in acute myeloid leukemia treated with lower intensity therapy.
  10. Lessons of nature from trisomy-8 myeloid neoplasia: the riddle of oncogenic clonal drives.
  11. Mutational profiling in acute myeloid leukemia.
  12. Real-world treatment patterns and outcomes in accelerated and blast-phase myeloproliferative neoplasms: Insights from a large multi-centre cohort analysis in the United Kingdom.
  13. Targeting WNK1 Releases Differentiation Block in Acute Myeloid Leukemia.
  14. Leukemic stem cell subtypes determine venetoclax resistance and therapeutic vulnerabilities in AML.
  15. CRISPR base editor screening identifies spectrum of MEN1 mutations impacting menin inhibitors in clinical trials.
  16. The role of RAS mutations in leukemia progression, differentiation, and drug resistance.
  17. MDM2 inhibitors in myeloid cancers: from basic biology to clinical use in myeloproliferative neoplasms.
  18. CAR T-cells targeting CD117 effectively eliminate mast cells in preclinical models of advanced systemic mastocytosis.
  19. Gilteritinib + chemotherapy in children with relapsed/refractory FLT3-ITD AML: results from the phase 1/2 SKIPPER trial.
  20. CD84 is a specific target for acute myeloid leukemia CAR-T cell therapy.
  21. High frequency of CD95+/CD45RA- regulatory T cells defines an immunosuppressive profile associated with MDS progression.
  22. AcTor, a novel mTOR stimulator, potentiates ixazomib for the treatment of acute myeloid leukemia.
  23. SOHO State of the Art Updates and Next Questions: Is Combination Therapy Here for Myelofibrosis?
  24. Targeting RBPMS selectively eliminates FOXO1-mediated stem cell signatures in mouse models of acute myeloid leukemia.
  25. Final results of nilotinib versus nilotinib combined with pegylated interferon alfa-2a as first-line therapy in chronic phase chronic myeloid leukaemia in France (PETALs): an open-label, multicentre, randomised phase 3 trial.
  26. Understanding the Molecular Mechanisms Underlying Anemia in Myelodysplastic Syndromes: From Erythropoiesis to New Therapeutic Approaches.
  27. ATP2B1 expression identifies human hematopoietic stem cells with superior repopulation and self-renewal.
  28. Venetoclax and gilteritinib combination for FLT3-mutated relapsed/refractory acute myeloid leukemia: a real-world single-center experience.
  29. The evolution of polyclonal competition in aging hematopoiesis.
  30. Procr+ endothelial progenitor cells govern hematopoiesis through fine-tuning mesenchymal stem cell niche signals.
  31. NAT10 maintains stem cell homeostasis by mitigating mRNA decay through an ac4C-independent mechanism.
  32. CDK14 is a critical regulator of haematopoietic stem and progenitor cell maintenance and post-transplantation proliferation.
  33. Bone Marrow Stem Cell Connexins: Misconceptions and New Insights.
  34. Pediatric blastic plasmacytoid dendritic cell neoplasms are molecularly defined by recurrent MYB rearrangements: clinical and molecular insights.
  35. The Evolution of Haematopoietic Models Through a Clonal Lens.
  36. Age distinguishes selection from causation in cancer genomes.
  37. Impact of thrombosis on disease progression, cancer and mortality in patients with essential thrombocythemia and polycythemia vera.
  38. Impact of donor and recipient EBV serostatus on transplant outcomes in patients with acute leukemia after haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide: Infectious Diseases Working Party EBMT retrospective study.
  1. Blood Adv. 2026 May 05. pii: bloodadvances.2025016208. [Epub ahead of print]
    Combining Menin and MEK inhibition to target poor prognosis KMT2A-rearranged RAS pathway-mutant acute myeloid leukemia.
    Nastassja Keora Scheidegger, Constanze Schneider, Gabriela Alexe, Yi-Cheng Wang, Todd A Alonzo, Allen Basanthakumar, Wallace A Bourgeois, Julia Dudkiewicz-Garbicz, Delan Khalid, Lucy A Merickel, Jennifer A Perry, Rhonda E Ries, Silvi Salhotra, Audrey Taillon, Alan S Gamis, Richard Aplenc, Marian H Harris, Mark Wunderlich, Scott A Armstrong, Jessica A Pollard, Soheil Meshinchi, Yana Pikman, Kimberly Stegmaier.
      KMT2A-rearranged (KMT2A-r) acute leukemias are especially prevalent in the pediatric population. KMT2A-fusion proteins drive leukemogenic gene expression through an interaction with a chromatin complex that includes the scaffold protein menin, giving rise to aggressive acute leukemias. RAS pathway mutations are also common in pediatric leukemia. In a cohort of 1750 patients enrolled on Children's Oncology Group (COG) trials, we identified RAS pathway mutations in 43% of AML cases. The presence of RAS pathway mutations in KMT2A-r AML was associated with a lower complete remission (CR) rate, poor event-free (EFS) and overall survival (OS), and early relapses. Given the inferior outcome observed for children with dual mutations, we next sought to identify efficacious targeted drug combinations for this subset of childhood leukemia. We evaluated RAS/MAPK targeting using the MEK1/2 inhibitor selumetinib in combination with the menin inhibitor revumenib. Treatment of AML cell lines and cultured leukemia cells from patient-derived xenograft (PDX) models resulted in a synergistic decrease in viability and promoted cell cycle arrest, apoptosis and downregulation of Myc targets in the combination compared to each drug alone. In vivo, the combination treatment of AML pediatric PDX models harboring KMT2A-r and RAS mutations reduced leukemia burden compared to single drug treatments, but without improving overall survival compared to menin inhibition alone. Our preclinical study suggests a potential targeted treatment combination for KMT2A-r and RAS pathway mutant leukemia, but one which will require further optimization. COG completed clinical trials AAML03P1, AAML0531, AAML1031 and C2961.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016208
  2. Leukemia. 2026 May 06.
    U2af1S34F and U2af1Q157R myeloid neoplasm-associated hotspot mutations induce distinct hematopoietic phenotypes in mice.
    Michael O Alberti, Sridhar Nonavinkere Srivatsan, Jin Shao, Dennis L Fei, Mengou Zhu, Claudia Cabrera Pastrana, Monique Chavez, Stefan P Tarnawsky, Sarah Grieb, Timothy A Graubert, Omar Abdel-Wahab, Matthew J Walter.
      Recurrent somatic mutations in the spliceosome genes SF3B1, SRSF2, and U2AF1 are frequently identified in patients with myeloid neoplasms, such as myelodysplastic syndromes. We characterized the in vivo consequences of expressing two hotspot mutations in U2AF1 that code for the S34F and Q157R substitutions. Our results indicate that the two mutations induce distinct hematopoietic phenotypes in mice, suggesting that the U2AF1S34F and U2AF1Q157R mutations should not be conflated as they may impact disease pathogenesis differently in patients. Mice expressing U2af1S34F have a more severe reduction in their blood and bone marrow cell counts and reduced stem cell repopulating ability, compared to mice expressing U2af1Q157R. The expression and splicing of target genes are largely unique between the mutations, in both mouse and human samples, potentially driving the phenotypic differences induced by either mutation. The two mutations co-occur with different gene mutations in patients and are not equally represented across myeloid neoplasms, suggesting that multiple mechanisms likely drive U2AF1-mutant disease pathogenesis. Collectively, our results support that U2AF1S34F and U2AF1Q157R mutations induce distinct hematopoietic, gene expression, and RNA splicing phenotypes in vivo. Larger population studies will be needed to determine if these phenotypic changes translate into clinico-pathologic differences in patients, warranting separate classification.
    DOI:  https://doi.org/10.1038/s41375-026-02974-7
  3. Nat Genet. 2026 May 04.
    Transposable elements shape stemness in normal and leukemic hematopoiesis.
    Giacomo Grillo, Bettina Nadorp, Aditi Qamra, Bryce Drylie, Amanda Mitchell, Christopher Arlidge, Ankita Nand, Naoya Takayama, Alex Murison, Seyed Ali Madani Tonekaboni, Komaldeep Kaur Kang, Andrea Arruda, Jean C Y Wang, Mark D Minden, Özgen Deniz, Héléna Boutzen, John E Dick, Mathieu Lupien.
      Despite most acute myeloid leukemia (AML) patients achieving complete remission after induction chemotherapy, two-thirds relapse within 5 years. AML follows a cellular hierarchy sustained by leukemia stem cells (LSCs), which drive tumor progression and relapse. Little is known about the genetic determinants driving LSCs stemness properties. By identifying chromatin variants from accessibility measurements across LSCs, hematopoietic stem cells and downstream progeny, we identified transposable elements (TEs) as genetic determinants of primitive versus mature populations. Accessibility at 121 TE subfamilies distinguished LSCs from mature leukemic cells and stratified AML patients by stemness and survival. Functional assays revealed that these TE subfamilies serve as docking sites for genome topology regulators or lineage-specific transcription factors, including LYL1 in LSCs. Chromatin editing established the necessity of accessibility at LTR12C elements to maintain LSC stemness. Thus, TEs regulate primitive versus mature cell states, with distinct subfamilies underlying stemness in normal versus leukemic stem cells.
    DOI:  https://doi.org/10.1038/s41588-026-02585-z
  4. Cell. 2026 May 01. pii: S0092-8674(26)00439-3. [Epub ahead of print]
    Genetic variation reveals a homeotic long noncoding RNA that modulates human hematopoietic stem cells.
    Peng Lyu, Gaurav Agarwal, Chun-Jie Guo, Adam Sychla, Wallace Bourgeois, Tianyi Ye, Chen Weng, Mateusz Antoszewski, Samantha Joubran, Alexis Caulier, Michael Poeschla, Scott A Armstrong, Silvi Rouskin, Vijay G Sankaran.
      The HOXA gene locus coordinates body patterning, hematopoiesis, and differentiation. While studying blood phenotype-associated variation within the HOXA locus, we identified a genetic variant, rs17437411, associated with globally reduced blood counts, protection from blood cancers, and variation in anthropometric phenotypes. We found that this variant disrupts the activity of a previously unstudied antisense long non-coding RNA (lncRNA) located between HOXA7 and HOXA9, which we named HOXA opposite-strand transcript, stem-cell regulator, antisense mid-cluster between loci (HOTSCRAMBL). The HOTSCRAMBL variant disrupts lncRNA function and reduces human hematopoietic stem cell (HSC) self-renewal. Mechanistically, HOTSCRAMBL enables appropriate expression and splicing of HOXA genes in HSCs, most notably HOXA9, in an SRSF2-dependent manner. Given the critical role of HOXA gene expression in some blood cancers, we also demonstrate that HOTSCRAMBL variation or deletion compromises HOXA-dependent acute myeloid leukemias. Collectively, we show how insights from human genetic variation can uncover critical regulatory processes required for effective developmental gene expression.
    Keywords:  HOXA9; SRSF2; clonal hematopoiesis; genetic variation; hematopoiesis; hematopoietic stem cell; leukemia; lncRNA; splicing
    DOI:  https://doi.org/10.1016/j.cell.2026.04.014
  5. Blood Adv. 2026 May 07. pii: bloodadvances.2025018902. [Epub ahead of print]
    Single cell long read genotyping of transcripts reveals discrete mechanisms of clonal evolution in post-MPN AML.
    Julian Grabek, Jasmin M Straube, Leanne Cooper, Rohit Halder, Ranran Zhang, Inken Dulige, Matthew A Barker, Will Gatehouse, Helen Christensen, Gerlinda Amor, Victoria Y Ling, Caroline McNamara, David M Ross, Andrew C Perkins, Megan J Bywater, Steven W Lane.
      Myeloproliferative neoplasms (MPNs) are caused by acquired mutations in hematopoietic stem and progenitor cells (HSPCs). The acquisition of additional mutations like TP53 and the overall mutational burden influence a patient's risk of disease progression toward lethal post-MPN acute myeloid leukemia (AML). Recent technological advancements in linking single-cell gene expression with genotype have improved our understanding of tumor heterogeneity. However, current methodologies have limitations in simultaneously genotyping low-expression genes (such as JAK2) alongside other pathogenic loci. To address this, we developed a novel long read genotyping pipeline of cDNA transcripts called LOTR-Seq, which can genotype the full length of expressed transcripts of 30 genes at once. Using LOTR-Seq, we genotyped HSPCs at the JAK2V617 locus in 9,075 single cells from eight patients with chronic phase MPN (CP-MPN) and in 5,016 cells from four patients with post-MPN AML. We then linked the mutations to the single cell transcriptome of 29,712 JAK2V617F-driven CP-MPN cells and 16,895 post-MPN AML cells. In our analysis of post-MPN AMLs, we identified nine mutated loci across six genes (JAK2, IDH1/2, TP53, SRSF2, U2AF1) and linked these mutations to specific transcriptional phenotypes. Overall, LOTR-Seq provides novel insights into the evolution of post-MPN AML.
    DOI:  https://doi.org/10.1182/bloodadvances.2025018902
  6. Blood. 2026 May 07. pii: blood.2025029923. [Epub ahead of print]
    How I utilize somatic alterations in the diagnosis, risk stratification, and therapy of hypocellular bone marrow failure.
    Emma M Groarke, Fernanda Gutierrez-Rodrigues, Bhavisha A Patel.
      Hypocellular bone marrow failure (BMF) may be acquired due to immune-mediated disease, the prototype being immune aplastic anemia (IAA), or inherited, due to germline defects in genes important for hematopoietic stem cells' function and maintenance (inherited bone marrow failure syndromes [IBMFS]). Proper diagnosis of the underlying etiology of hypocellular bone marrow failure, particularly distinguishing immune AA, myelodysplastic syndrome (MDS) (most relevant in this setting, hypoplastic MDS [MDS-h]), and the IBMFS, is important given the differences in clinical management. Clonal hematopoiesis (CH), in this context comprising somatic mutations or chromosomal abnormalities, is incorporated into standard algorithms for classification, risk stratification, and treatment decisions for hematologic malignancies, but the clinical significance in BMF is not well established. Disease-specific clonal signatures have been reported across the BMF spectrum, and here we show how distinct patterns of CH can aid in distinguishing different etiologies of hypocellular BMF. Additionally, detection of somatic alterations in many BMF disorders can estimate risk for secondary myeloid neoplasms, guide surveillance and, in some instances, allow for early therapeutic intervention.
    DOI:  https://doi.org/10.1182/blood.2025029923
  7. Leukemia. 2026 May 05.
    MECOM promotes leukemia progression and inhibits mast cell differentiation through functional competition with GATA2.
    Kohei Iida, Mayuko Nakanishi, Jakushin Nakahara, Shuhei Asada, Tomoya Isobe, Tomohiro Yabushita, Tsuyoshi Fukushima, Yosuke Tanaka, Manabu Ozawa, Yasuhiro Yamada, Toshio Kitamura, Keita Yamamoto, Susumu Goyama.
      MECOM is a transcription factor critical for the maintenance of hematopoietic stem cells (HSCs) and the pathogenesis of myeloid leukemia. Germline mutations clustered in the C-terminal zinc finger domain (ZFD) of MECOM are known to cause MECOM-associated syndromes, involving bone marrow failure and skeletal anomalies. However, the molecular consequences of these mutations and the precise downstream mechanisms of MECOM remain elusive. Here, we demonstrate that the C-terminal ZFD serves as the dominant DNA-binding module of MECOM, and that disease-associated mutations abrogate its DNA-binding capacity. Mechanistically, we reveal that MECOM functionally antagonizes GATA2 via C-terminal ZFD-mediated DNA binding and recruitment of the corepressor CtBP. This repression promotes myeloid leukemogenesis while suppressing mast cell differentiation. Furthermore, we generated a knockin mouse model harboring a C-terminal ZFD mutation, which successfully recapitulated the clinical phenotypes of MECOM-associated syndromes, including reduction of HSCs and B cells. Collectively, our findings define C-terminal ZFD mutations as loss-of-function mutations with impaired DNA binding, uncover the MECOM-GATA2 axis as a key regulatory pathway, and provide a valuable mouse model for understanding MECOM-associated syndromes.
    DOI:  https://doi.org/10.1038/s41375-026-02977-4
  8. Haematologica. 2026 May 07.
    Myelodysplastic syndrome with concomitant SF3B1 mutation and deletion of chromosome 5 long arm: outcomes and response to treatment.
    Rami Komrokji, Zaker Schwabkey, Zena Komrokji, Najla Al Ali, Luis Aguirre, Maximilian Stahl, Somedeb Ball, Emily Mason, Michael Savona, Valeria Santini, Angela Consagra, Uwe Platzbecker, Anne Sophie Kubasch, Yazan Madanat, Pierre Fenaux, Lin-Pierre Zhao, Mikkael A Sekeres, Namrata Chandhok, Matteo Della Porta, Luca Lanino, Amy DeZern, David Sallman, Eric Padron, Zhuoer Xie, Koji Sasaki, Kensuke Takaoka, Akhil Jain, Monica Del Rey Gonzalez, Maria Diez Campelo, Guillermo Garcia-Manero.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2025.300396
  9. Cancer. 2026 May 15. 132(10): e70434
    Prognostic impact of ASXL1 mutations in acute myeloid leukemia treated with lower intensity therapy.
    Jennifer Marvin-Peek, Courtney D DiNardo, Sanam Loghavi, Farhad Ravandi, Gautam Borthakur, Naval G Daver, Tapan M Kadia, Elias Jabbour, Andrew Dunbar, Guilin Tang, Nicholas J Short, Fadi G Haddad, Hussein A Abbas, Eitan Kugler, Abhishek Maiti, Ghayas C Issa, Koichi Takahashi, Kapil Bhalla, Naveen Pemmaraju, Yesid Alvarado, Elizabeth J Shpall, Uday Popat, Jeremy Ramdial, Richard E Champlin, Hagop M Kantarjian, Guillermo Garcia-Manero, Jayastu Senapati.
       BACKGROUND: ASXL1 mutations (ASXL1MUT) are common in acute myeloid leukemia (AML) and have historically conferred an adverse prognosis with intensive chemotherapy. Given the increasing use of venetoclax (VEN)-based lower intensity therapy (LIT), the European LeukemiaNet introduced a four-gene genetic risk classifier in 2024 that categorizes ASXL1 MUT as favorable risk in the absence of FLT3-ITD, RAS, and TP53 mutations. However, the prognostic significance of ASXL1MUT across different contemporary LIT+VEN backbones remains controversial.
    METHODS: A retrospective analysis in 554 adults with newly diagnosed AML treated with LIT was conducted, stratified by ASXL1 mutation status and treatment backbone.
    RESULTS: Within the European LeukemiaNet 2024 favorable-risk strata, ASXL1MUT were associated with lower response rates and inferior overall survival, with outcomes more closely resembling those of intermediate-risk disease. Survival differences were most pronounced in patients treated with cladribine plus low-dose cytarabine and VEN, but inferior outcomes were also observed with hypomethylating agent + VEN-based regimens. On multivariable analyses accounting for age, cytogenetics, co-mutations, treatment backbone, and stem cell transplantation, ASXL1MUT remained independently associated with inferior overall survival.
    CONCLUSIONS: Collectively, these findings suggest that ASXL1MUT AML may be more appropriately classified as intermediate risk in the context of LIT+VEN-based therapy, with the depth of impact influenced by the specific LIT backbone.
    Keywords:  AML; ASXL1; acute myeloid leukemia; low‐intensity therapy; venetoclax
    DOI:  https://doi.org/10.1002/cncr.70434
  10. Haematologica. 2026 May 07.
    Lessons of nature from trisomy-8 myeloid neoplasia: the riddle of oncogenic clonal drives.
    Hussein Awada, Arda Durmaz, Luca Guarnera, Zachary Brady, Yasuo Kubota, Serhan Unlu, Carmelo Gurnari, Carlos Bravo-Perez, Hassan Awada, Torsten Haferlach, Jaroslaw P Maciejewski, Valeria Visconte.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2026.300822
  11. Haematologica. 2026 May 01. 111(5): 1511-1512
    Mutational profiling in acute myeloid leukemia.
    Courtney D DiNardo.
      
    DOI:  https://doi.org/10.3324/haematol.2026.289405
  12. Br J Haematol. 2026 May 03.
    Real-world treatment patterns and outcomes in accelerated and blast-phase myeloproliferative neoplasms: Insights from a large multi-centre cohort analysis in the United Kingdom.
    UK Blood Cancer Research Network MPN Clinical Study Group
      This UK-based retrospective analysis describes real-world treatment patterns and outcomes in 175 patients with accelerated (AP, n = 69) or blast-phase (BP, n = 106) 'Philadelphia-negative' myeloproliferative neoplasms (MPN-AP/BP) diagnosed between 2013 and 2025. Median age at transformation was 71 years. With a median follow-up of 45.2 months, median overall survival (OS) was 14.9 months, significantly worse for MPN-BP (6.7 months) versus MPN-AP (25.3 months). Treatment selection was heterogeneous across centres. Intensive chemotherapy (IC) improved outcomes only when followed by allogeneic haematopoietic stem cell transplant (allo-HSCT) (median OS 24.7 months). Ruxolitinib-based regimens, particularly combined with azacitidine, showed acceptable activity in AP (median OS 27.2 months). Venetoclax-based regimens achieved a median OS of 14.9 months across the cohort. Multivariable analysis identified IC and venetoclax-based therapy as independently associated with better outcomes, reflecting patient selection, while TP53 mutations predicted inferior survival. IC carried high rates of febrile neutropenia and sepsis; venetoclax was associated with prolonged cytopenias. This study confirms the poor prognosis of MPN-AP/BP, the absence of a unified UK consensus approach and the need for improved therapies and prospective studies to determine optimal treatment approaches for this challenging cohort.
    Keywords:  MPN; accelerated phase; blast phase; myeoproliferative neoplasms; real world
    DOI:  https://doi.org/10.1111/bjh.70511
  13. bioRxiv. 2026 Apr 25. pii: 2026.04.22.720037. [Epub ahead of print]
    Targeting WNK1 Releases Differentiation Block in Acute Myeloid Leukemia.
    Jordan D Cress, Emily M Katoni, Parameswaran Ramakrishnan.
      Impaired differentiation is a hallmark of Acute Myeloid Leukemia (AML). Current differentiation therapies benefit only a small subset of AML patients, leaving a substantial gap in care for other subtypes. Identifying novel molecular drivers of maturation arrest is critical to expand differentiation induction to a broader range of AML patients. This study addresses this unmet clinical need, by identifying With-no-Lysine(K) kinase 1 (WNK1) as a novel regulator of AML differentiation arrest. We show that WNK1 expression and activity are elevated in AML patients. WNK1 inhibition induced differentiation accompanied by decreased growth and survival of AML cell lines and patient cells. It also inhibited self-renewal of AML patient cells in vitro and elicited significant anti-tumor activity in vivo in mouse models. Mechanistically, WNK1 inhibition derepressed the MEK-ERK-C/EBPβ signaling axis and increased the expression of myeloid differentiation genes. Our findings reveal a novel role of WNK1 in promoting AML through differentiation arrest, posing WNK1 inhibition as a potential approach for AML differentiation therapy.
    DOI:  https://doi.org/10.64898/2026.04.22.720037
  14. Cell Stem Cell. 2026 May 07. pii: S1934-5909(26)00152-9. [Epub ahead of print]
    Leukemic stem cell subtypes determine venetoclax resistance and therapeutic vulnerabilities in AML.
    Alexander Waclawiczek, Aino-Maija Leppä, Simon Renders, Ines Bergerweiss, Karolin Stumpf, Barbara Betz, Susanna Gabrowski, Frank Y Huang, Maria-Eleni Lalioti, Bendix Hempel, Markus Sohn, Heikki Kuusanmäki, Vera Thiel, Julia M Unglaub, Rabia Shahswar, Sarah Richter, Maike Janssen, Darja Karpova, Elisa Donato, Halvard Bonig, Christoph Röllig, Simon Raffel, Michael Heuser, Michael Hundemer, Mika Kontro, Ann-Kathrin Eisfeld, Tim Sauer, Nina Cabezas-Wallscheid, Carsten Müller-Tidow, Andreas Trumpp.
      The BCL-2 inhibitor venetoclax has transformed the treatment of acute myeloid leukemia (AML), but relapse due to resistance of leukemic stem cells (LSCs) remains a major challenge. By molecular and functional profiling of LSCs from >150 patients, we identify four LSC subtypes. These mirror distinct hematopoietic lineage stages, which determine the expression ratio between the venetoclax target BCL-2 and resistance-inducing proteins MCL-1 and BCL-xL (MAC-score). Longitudinal analyses reveal that venetoclax resistance mostly arises in LSCs through plasticity toward a megakaryocytic/erythroid-progenitor (MEP)-LSC state that switches survival dependency from BCL-2 to BCL-xL. In rare cases, mature monocytic/dendritic (MoDe)-LSCs, found within LAMP5+ monocytic AMLs, drive venetoclax resistance. LSC subtyping improves genetic risk stratification and provides subtype-specific therapies: venetoclax-resistant MEP-LSCs respond to BCL-xL inhibitors, whereas MoDe-LSCs are sensitive to MEK1/2 inhibition. Our findings reveal four distinct LSC types with unique vulnerabilities and propose biomarker-guided treatment strategies that complement genetic profiling to overcome venetoclax resistance.
    Keywords:  BCL-2; MAC-score; acute myeloid leukemia; azacitidine; chemotherapy; leukemic stem cells; personalized medicine; plasticity; therapy resistance; venetoclax
    DOI:  https://doi.org/10.1016/j.stem.2026.04.012
  15. Nat Commun. 2026 May 09.
    CRISPR base editor screening identifies spectrum of MEN1 mutations impacting menin inhibitors in clinical trials.
    Wallace Bourgeois, Hannah E Rice, Daniela V Wenge, Florian Perner, Hong Yue, Brandon D Regalado, George Wan, Jan C Schroeder, Alba Sommerschield, Charlie Hatton, Shivendra Singh, Sweta Singh, Shipra Bijpuria, Brian M McKeever, William H Miller, Jordan F Safer, Sumaiya Iqbal, Jennifer A Perry, Eric S Fischer, John G Doench, Gerard M McGeehan, Jevon A Cutler, Scott A Armstrong.
      Menin inhibitors have entered clinical trials for histone lysine methyltransferase 2 A (KMT2A)-rearranged and nucleophosmin 1 (NPM1)-mutant acute leukemias and are demonstrating promising activity. CRISPR base editor screening previously predicted several MEN1 (menin) mutations that have arisen in patients receiving SNDX-5613 and confer resistance. The extent to which MEN1 mutations will impact each menin inhibitor is mostly unknown. Here we show that CRISPR base editor screens can be leveraged to profile the MEN1 mutations that may impact five different menin inhibitors in clinical trials. We identify shared (M327I/V/T, G331D) and inhibitor-specific (C334R, E368K/V, V372A) resistance mutations. Co-crystal structures of menin bound to each menin inhibitor suggest resistance mechanisms related to how each inhibitor engages the KMT2A binding pocket of menin. Orthogonal in vitro and in vivo MEN1 mutation generation under therapeutic pressure suggest the MEN1 mutations identified with CRISPR base editor screening are likely to arise and impact all menin inhibitors.
    DOI:  https://doi.org/10.1038/s41467-026-72685-1
  16. Leuk Res Rep. 2026 ;25 100589
    The role of RAS mutations in leukemia progression, differentiation, and drug resistance.
    Congfa Jiang, Hangxuan Wang, Jiaxin Zhao, Yuwei Xu, Shiwei Duan.
      Mutations in the RAS gene family (NRAS, KRAS) are critical drivers of late-stage acute myeloid leukemia (AML) progression. They are frequently detected in relapsed/refractory AML and AML transformed from myelodysplastic syndrome (MDS). Occurring as late-stage genetic events, RAS mutations synergize with early drivers to promote leukemogenesis. While mutually exclusive with FLT3-ITD mutations, they coexist with KIT, RUNX1, CEBPA mutations and MLL rearrangements. Granulocyte-monocyte progenitors (GMPs) serve as the cellular origin for RAS-mutant leukemia stem cells (LSCs). Ultimately, RAS mutations drive monocytic differentiation of LSCs and venetoclax (VEN) resistance through BCL-2 family rewiring. Beyond AML, they are hallmark genetic lesions in juvenile myelomonocytic leukemia (JMML) and present in 15%-20% of pediatric acute lymphoblastic leukemia (ALL) cases. Here, we propose a comprehensive pathogenic model and targeted therapeutic framework focusing on RAS, MCL-1, BCL2L1 to overcome drug resistance and improve patient outcomes.
    Keywords:  ALL; AML; JMML; RAS mutations; Venetoclax resistance
    DOI:  https://doi.org/10.1016/j.lrr.2026.100589
  17. Leukemia. 2026 May 05.
    MDM2 inhibitors in myeloid cancers: from basic biology to clinical use in myeloproliferative neoplasms.
    Haifa K Al-Ali, Sarah T Heidel, Francesca Palandri, Florian H Heidel.
      Pharmacologic targeting of murine double minute 2 (MDM2) represents one of the most compelling strategies for therapeutic reactivation of wild-type p53 in hematologic malignancies. The MDM2-p53 autoregulatory loop is a central regulator of cellular stress responses, and in myeloid neoplasms-including acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN)-p53 is frequently retained but functionally suppressed through MDM2 overexpression and oncogenic signaling, notably via JAK-STAT activation. Over the past decade, successive generations of MDM2 inhibitors have translated structural and mechanistic insights into clinical investigation, yielding critical lessons regarding dosing paradigms, hematologic toxicity, biomarker-driven patient selection, and mechanisms of resistance, including TP53-mutant clonal selection. While early phase III trials in AML were negative, recent studies in myelofibrosis demonstrate clinically meaningful spleen, symptom, and molecular responses, supporting disease-modifying potential in TP53-wild-type settings. Adaptive platform designs and rational combinations with JAK inhibitors, BCL-2 antagonists, and interferons have further refined therapeutic strategies. Emerging MDM2 degraders and next-generation agents aim to overcome feedback limitations and improve therapeutic index. This review integrates mechanistic foundations, clinical development, resistance biology, and future directions, highlighting how decades of basic science have reshaped p53 reactivation into a precision therapeutic paradigm in myeloid disease.
    DOI:  https://doi.org/10.1038/s41375-026-02975-6
  18. Leukemia. 2026 May 07.
    CAR T-cells targeting CD117 effectively eliminate mast cells in preclinical models of advanced systemic mastocytosis.
    Anne Kaiser, Veronika Lysenko, Renier Myburgh, Laura Volta, Christian Pellegrino, Alexandre P A Theocharides, Deborah Christen, Jens Panse, Marco M Bühler, Michel Arock, Joseph Butterfield, Marcelo A S de Toledo, Peter Valent, Martin Zenke, Tim H Brümmendorf, Markus G Manz.
      Systemic mastocytosis (SM) is characterized by uncontrolled expansion of neoplastic mast cells (MCs) and their accumulation in various tissues and organs, ranging from indolent variants to more advanced forms (advSM). Although several MC- and SM-expressed cell surface antigens have been identified, no immune therapy has been developed for advSM so far. The receptor tyrosine kinase KIT (CD117) is highly expressed on MCs, exceeding the levels of expression on hematopoietic stem and progenitor cells (HSPC). Therefore, targeting CD117 in advSM could be of therapeutic value. In this study, we assessed the therapeutic potential of anti-CD117 chimeric antigen receptor (CAR) T-cells to target neoplastic MCs in SM. In vitro, anti-CD117-CAR T-cells efficiently lysed several SM-related human MC cell lines, MCs differentiated from SM patient-derived induced pluripotent stem (iPS) cells, and neoplastic bone marrow cells obtained from SM patients. Furthermore, in immunocompromised mice engrafted with an advSM-like MC cell line, repetitive applications of anti-CD117-CAR T-cells were able to inhibit MC expansion. These data may pave the way for the development of anti-CD117-CAR T-cell therapies in advSM.
    DOI:  https://doi.org/10.1038/s41375-026-02968-5
  19. Blood Adv. 2026 May 08. pii: bloodadvances.2026020144. [Epub ahead of print]
    Gilteritinib + chemotherapy in children with relapsed/refractory FLT3-ITD AML: results from the phase 1/2 SKIPPER trial.
    Philip Connor, Raul C Ribeiro, Albert Catala, Alice Norton, Michael M Schündeln, Nahla Hasabou, David Delgado, Alexandra Natalie Heinloth, Jason E Hill, Stanley C Gill, Theophile Bigirumurame, Sarah K Tasian, Franco Locatelli.
      Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) occurs in ~15% of pediatric patients with acute myeloid leukemia (AML) and is associated with high relapse risk with conventional chemotherapy. Gilteritinib is a selective, next-generation FLT3 inhibitor (FLT3i) approved for adults with relapsed/refractory FLT3‑mutated AML, but pediatric-specific data remain limited. The multi-national phase 1/2 SKIPPER study evaluated gilteritinib combined with fludarabine and cytarabine chemotherapy and granulocyte colony‑stimulating factor (FLAG) in children and adolescents/young adults with relapsed/refractory FLT3‑ITD AML. Nine patients, aged 8-15 years, were enrolled in phase 1 of the study between 2020 and 2023. Recruitment challenges, including disease rarity, off‑label FLT3i availability, and competing trials, led to study termination after phase 1. The composite complete remission rate in the study population was 66.7% (95% confidence interval: 29.9%-92.5%). Two‑year event‑free and overall survival probability was 41.7% and 55.6%, respectively. Treatment‑emergent adverse events, most commonly reversible hepatic enzyme elevations and cytopenias, were consistent with known toxicity profiles of gilteritinib and FLAG. Pharmacokinetic parameters were comparable to those of adults, and pharmacodynamic plasma inhibitory activity assays confirmed sustained FLT3 inhibition. No dose‑limiting toxicities were observed, and the recommended phase 2 dose of gilteritinib was established at 2 mg/kg/day for patients ≥2 years old. The gilteritinib and FLAG regimen had manageable safety, induced high remission rates, and enabled allogeneic hematopoietic stem cell transplant for several patients. Although limited by a small sample size, these findings support further evaluation of gilteritinib in pediatric patients with FLT3-mutated AML, particularly in frontline settings (ClinicalTrials.gov Identifier: NCT04240002).
    DOI:  https://doi.org/10.1182/bloodadvances.2026020144
  20. Nat Commun. 2026 May 08.
    CD84 is a specific target for acute myeloid leukemia CAR-T cell therapy.
    Martina Pigazzi, Silvia Merlini, Ambra Da Ros, Olivia Marini, Giovanni Faggin, Nicolò Fortuna, Raffaele Mattera, Barbara Buldini, Paolo Rizzardi, Soheil Meshinchi, Giuseppe Basso, Franco Locatelli, Alessandra Biffi.
      Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of hematologic malignancies, yet its application to acute myeloid leukemia (AML) remains challenging due to the scarcity of disease-specific antigens. The identification of a highly selective target is crucial to enhance efficacy while minimizing off-tumor toxicity. Here, we identify CD84 as a promising target for AML immunotherapy, displaying a unique expression profile: it is robustly and stably expressed by blasts, particularly in relapsed disease, and negligible on normal hematopoietic stem/progenitor cells. This profile renders CD84 an ideal target, with potential for improved therapeutic precision and potency, and with reduced risk of off-target effects and toxicity. To assess its potential, we generate CD84-directed CAR-T cells and test them in vitro and in vivo on clinically relevant models. The engineered cells exhibit potent cytotoxicity against CD84-expressing AML cell lines and patient-derived xenograft (PDX) cells, eliminating leukemic blasts even with low CD84 expression. In AML-PDX models, CAR-T treatment leads to sustained reduction of leukemia burden, doubling the survival of the treated animals compared to controls. No downregulation of CD84 expression on the blasts in the treated models is seen. Importantly, CD84 CAR-T cells spare normal hematopoietic stem/progenitor cells that after treatment retain their repopulation potential in humanized models. These findings establish CD84 as a target for AML immunotherapy and provide a compelling rationale for clinical development of CD84-directed approaches that may address an urgent need for treatment in aggressive and refractory AML.
    DOI:  https://doi.org/10.1038/s41467-026-72361-4
  21. Br J Haematol. 2026 May 04.
    High frequency of CD95+/CD45RA- regulatory T cells defines an immunosuppressive profile associated with MDS progression.
    Romain Vazquez, Nicolas Deredec, Ismael Boussaid, Pierre Boncoeur, Camille Knosp, Amandine Houvert, Loria Zalmai, Chloe Friedrich, Carole Almire, Charles Dussiau, Lise Willems, Rudy Birsen, Justine Decroocq, Didier Bouscary, Olivier Kosmider, Shahram Kordasti, Michaela Fontenay, Yannick Simoni, Nicolas Chapuis.
      Dynamic interactions between mutated haematopoietic cells and immune cells are key drivers of myelodysplastic neoplasms (MDS) initiation and progression. Regulatory T cells (Tregs) are central mediators of immunosuppression in MDS. We thus aimed to characterize Treg subpopulations in the bone marrow (BM) of MDS patients and to explore their clinical significance. Using mass cytometry and an unbiased multidimensional analytical approach, we first confirmed the presence in MDS BM of two Treg subsets, including the highly activated CD95+/CD45RA- subpopulation previously reported in aplastic anaemia. We then prospectively analysed Tregs distribution in BM of 113 MDS patients at diagnosis and during follow-up. While Treg proportions among CD4+ T cells were unchanged, CD95+/CD45RA- Tregs were significantly expanded in the BM of both low- and high-risk MDS patients. CD95+/CD45RA- Tregs accumulated during disease evolution but remained stable in patients responding to hypomethylating agents. At diagnosis, CD95+/CD45RA- Tregs levels correlated with specific clinical features: low CD95+/CD45RA- Tregs with TET2/IDH mutations and autoimmune manifestations; high CD95+/CD45RA- Tregs with an increased risk of disease progression independently of the IPSS-R and the IPSS-M. Our findings suggest that profiling Treg subpopulations at diagnosis could improve MDS risk stratification and guide immunosuppressive therapeutic decisions.
    Keywords:  myelodysplastic neoplasms; regulatory T cells
    DOI:  https://doi.org/10.1111/bjh.70504
  22. Res Sq. 2026 Apr 23. pii: rs.3.rs-9405584. [Epub ahead of print]
    AcTor, a novel mTOR stimulator, potentiates ixazomib for the treatment of acute myeloid leukemia.
    Shakti P Pattanayak, Odai Darawshi, Omid Hajihassani, Jordan M Winter, Nicole Weiler, Melanie Ott, Florian Rothweiler, Jindrich Cinatl, Martin Michaelis, Daniel J Lindner, Thomas D Green, Polina Krassovskaia, Raphael T Aruleba, Kelsey H Fisher-Wellman, Jason A Mears, David Wald, Leif A Eriksson, Boaz Tirosh.
      Background mTORC1 activity is oncogenic. However, in the presence of chemotherapy, suppression of mTORC1 is cytoprotective. mTOR suppression requires an intact tuberous sclerosis complex (TSC), composed of TSC1, TSC2 and TBC1D7. Small molecules that activate mTOR by blocking the TSC are lacking. Methods We applied in silico docking and medicinal chemistry to generate AcTor, a potential first-of-its-kind TSC2 inhibitor. Because inhibition of TSC2 results in increased sensitivity to proteasome inhibitors, we combined AcTor and the proteasome inhibitor ixazomib (IXZ) in various cancer cell types. Results Potentiation of cytotoxic activity of IXZ by AcTor was observed across multiple acute myeloid leukemia (AML) cell lines and primary patient samples. The combination triggered a collapse of mitochondrial respiratory capacity, loss of mitochondrial membrane potential, accumulation of ROS and apoptosis. These attributes increased in drug-resistant AML. Transcriptomic profiling revealed that AcTor alone induced anabolic and oxidative phosphorylation programs, whereas AcTor/IXZ redirected the signaling towards stress-associated and pro-apoptotic transcriptional states, including a p53 pathway signature. In vivo studies revealed reduction in AML burden, depletion of blasts and of leukemic stem cells, and retention of activity upon relapse. AcTor/IXZ was equally potent in a TP53 -mutated patient-derived xenograft model, exceeding the efficacy of standard-of-care. Conclusions As a TSC2 inhibitor, AcTor should not be used alone in cancer. When combined with proteasome inhibitors, the pharmacodynamics of AcTor shifts towards the development of a mitochondrial catastrophe in AML, which is durable, broad range, agnostic to TP53 mutations and to the acquisition of resistance to common clinical anti-AML drugs.
    DOI:  https://doi.org/10.21203/rs.3.rs-9405584/v1
  23. Clin Lymphoma Myeloma Leuk. 2026 Apr 08. pii: S2152-2650(26)00102-3. [Epub ahead of print]
    SOHO State of the Art Updates and Next Questions: Is Combination Therapy Here for Myelofibrosis?
    Megan Metzger, Charles Hertz, John Mascarenhas.
      Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by progressive cytopenias, splenomegaly, and constitutional symptoms. The hallmark of MF pathophysiology is constitutive activation of JAK/STAT signaling, which, in the majority of cases, is associated with an acquired mutation in one of three driver mutations, JAK2, CALR, or MPL. Our growing understanding of the molecular biology of MPNs has resulted in regulatory approval of four JAK inhibitors (JAKi), which have demonstrated efficacy in improving symptom burden and reducing spleen size. Despite clear benefits of JAKi therapy, including evidence of improved survival, these therapeutic interventions have not established an ability to modify disease in terms of resolution of bone marrow fibrosis or molecular remissions. Therefore, recent emphasis has been on the development of novel therapies with informed targets outside of the JAK/STAT signaling pathway. Moreover, combination approaches utilizing JAK and non-JAK targeting agents underscore the potential for disease modification along with deeper and more durable clinical responses. Emerging combination strategies and their clinical development will be reviewed here, including investigations that pair JAKi therapy with BCL-2 family inhibitors, BET inhibitors, restored p53 cell death signals, telomerase inhibitors, PIM1 kinase inhibitors, and mutant CALR targeted therapies. While several combination clinical trials suggest improved spleen and symptom responses and the possibility of disease modification, toxicity profiles and optimal sequencing remain areas of active investigation.
    Keywords:  CALR targeted therapies; Combination strategies; Disease modification; Novel therapies; Synergy
    DOI:  https://doi.org/10.1016/j.clml.2026.04.002
  24. Sci Transl Med. 2026 May 06. 18(848): eadv8951
    Targeting RBPMS selectively eliminates FOXO1-mediated stem cell signatures in mouse models of acute myeloid leukemia.
    Ping Liu, Sulin Zhang, Bing-Yi Chen, Binhe Chang, Yilun Jiang, Xiya Li, Xinchi Chen, Zi-Juan Li, Ruirui Yang, Xiaoning Wang, Chun-Hui Xu, Xiaomeng Liu, Na Liu, Yuanyuan Jia, Peng-Cheng Yu, Yong Wang, Li-Juan Zong, Cheng-Long Hu, Hui Hou, Duanhua Cao, Xutong Li, Chu-Han Deng, Yi-Yi Ren, Mu-Ying Zhao, Xinyi Ma, Rongrong Cui, Dan Teng, Miao Chen, Roujia Wang, Jiacheng Jin, Shi-Yu Jiang, Xiaojing Yan, Kai Xue, Qunling Zhang, Jianfeng Li, Enyong Dai, Shuhong Shen, Zhikai Wang, Xueshi Ye, Jin Zhang, Yu Liu, Wenguo Cui, Min Lu, Wei-Li Zhao, Chun-Kang Chang, Peng-Cheng He, Zhu Chen, Sai-Juan Chen, Mingyue Zheng, Xiao-Jian Sun, Lan Wang.
      Leukemia is a malignant tumor with a high recurrence rate and poor prognosis for patients. Thus, there is an urgent need to explore new therapeutic targets that play critical roles in leukemogenesis but have little effect on normal hematopoietic cells. Here, we show that RNA binding protein with multiple splicing (RBPMS), which is highly expressed in acute myeloid leukemia (AML) and associated with poor prognosis of AML, plays critical roles in leukemogenesis. Our study shows that inhibition of RBPMS inhibits self-renewal of leukemia-initiating cells (LICs) and leukemia development but has little effect on normal hematopoiesis. Mechanistically, RBPMS recruits the N6-methyladenosine (m6A) reader insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3), which promotes the stability of the forkhead box O1 (FOXO1) mRNA in an m6A-dependent manner. Moreover, RBPMS contributes to the progression of leukemia by directly binding to FOXO1 and promoting FOXO1-regulated glycolysis. Overexpression of FOXO1 has been shown to reverse RBPMS inhibition-induced phenotypes in both leukemic cells and mouse models. We also designed a specific inhibitor of RBPMS that has therapeutic effects in AML patient-derived xenograft (PDX) models. We therefore highlight RBPMS as a promising drug target for leukemia therapy.
    DOI:  https://doi.org/10.1126/scitranslmed.adv8951
  25. Lancet Haematol. 2026 May;pii: S2352-3026(26)00043-8. [Epub ahead of print]13(5): e315-e326
    Final results of nilotinib versus nilotinib combined with pegylated interferon alfa-2a as first-line therapy in chronic phase chronic myeloid leukaemia in France (PETALs): an open-label, multicentre, randomised phase 3 trial.
    Franck E Nicolini, Gabriel Etienne, Françoise Huguet, Aude Charbonnier, Gabrielle Roth-Guépin, Martine Escoffre-Barbe, Viviane Dubruille, Hyacinthe Johnson-Ansah, Philippe Rousselot, Laurence Legros, Anne Parry, Lydia Roy, Valérie Coiteux, Pascal Lenain, Jean-Christophe Ianotto, Charlotte Doublet, Corentin Orvain, Marion Simonet-Boissard, Marie-Lorraine Chrétien, Amélie Penot, Mathieu Meunier, Shanti Amé, Eric Hermet, Philippe Quittet, Simona Lapusan, Vérane Schwiertz, Jean-Michel Cayuela, Carole Mauté, Delphine Réa, Stéphane Morisset, François-Xavier Mahon, Stéphanie Dulucq.
       BACKGROUND: Second generation tyrosine kinase inhibitors (TKIs) have improved response rates in patients with chronic phase chronic myeloid leukaemia (CP-CML). Phase 2 trials demonstrated increased deep molecular response rates when combining second generation TKIs with pegylated interferon alfa (Peg-IFN). This trial aimed to evaluate the efficacy and the safety of combining nilotinib with Peg-IFN alfa-2a in patients with newly diagnosed CP-CML.
    METHODS: In PETALs, this open-label, randomised, multicentre phase 3 trial, we enrolled patients with newly diagnosed CP-CML from 27 French academic institutions via a centrally-generated electronic system in a 1:1 ratio to two groups: 300 mg oral nilotinib alone twice a day (the nilotinib only group) or 300 mg nilotinib twice a day combined with subcutaneous Peg-IFN (30 μg per week for the first month of treatment and 45 μg per week thereafter) for a maximum of 2 years. The randomly allocated patients were stratified by their Sokal index and European Treatment and Outcome Study long-term survival index. Eligible patients had major BCR::ABL1 transcripts, an Eastern Cooperative Oncology Group performance score of two or lower, who had never received TKIs, and were aged between 18 and 65 years. The primary endpoint was the cumulative rate of molecular response 4·5 (MR4·5; defined as BCR::ABL1 international scale [IS] of 0·0032% and lower), analysed in the intention-to-treat population (n=200). This trial is registered at ClinicalTrials.gov, NCT02201459, and is completed.
    FINDINGS: 205 patients were enrolled between Aug 6, 2014, and Sept 29, 2016, after which five patients were declared ineligible and excluded, resulting in 200 patients being randomly allocated (99 to the nilotinib group and 101 to the combination group). The median age at diagnosis was 45 years (IQR 36-55); 130 patients (65%) were male and 70 (35%) were female. Median follow-up in this cohort was 67 months (IQR 32·6-70·6). The primary objective was met, with higher rates of MR4·5 in the combination group (24% [95% CI 16·0-34·1] vs 15% [8·6-24·2], p=0·048) at month 12. There were equivalent grade 3-4 haematological side effects in the both groups (14 vs 14) with a predominance for grade 3-4 thrombocytopenia without haemorrhages (six in the combination group vs five in the nilotinib group). Psychiatric grade 3-4 events occurred in six (6%) patients in the combination group (including three unsuccessful suicide attempts) compared with five (5%) in the nilotinib group (including one unsuccessful suicide attempt). Six vascular events also occurred in six patients in the combination group and seven vascular events in five patients in the nilotinib group (all grades 3-4).
    INTERPRETATION: In this setting, Peg-IFN combined with nilotinib induced higher initial rates of MR4·5 compared to TKI monotherapy, despite additional side effects. The onset of psychiatric events might promote immediate cease of Peg-IFN and psychiatrist advice Whether this early molecular response translates into sustained treatment-free survival should be studied in a randomised trial sufficiently powered for this outcome.
    FUNDING: Novartis Pharma.
    DOI:  https://doi.org/10.1016/S2352-3026(26)00043-8
  26. Blood Cancer Discov. 2026 May 06. OF1-OF12
    Understanding the Molecular Mechanisms Underlying Anemia in Myelodysplastic Syndromes: From Erythropoiesis to New Therapeutic Approaches.
    Vera Adema, Francesco Pesce, Guillermo Garcia-Manero, Valeria Santini, Simona Colla.
      Minimizing the transfusion burden is one of the primary clinical goals for most patients with myelodysplastic syndromes (MDS), which are incurable hematopoietic stem cell neoplasms. In some patients, supportive red blood cell transfusions can lead to clinical improvement, but frequent transfusions induce iron overload, which can have detrimental effects on cardiac and hepatic function, affect patients' quality of life, and incur additional healthcare costs. In this review, we summarize how erythropoiesis is regulated under steady-state conditions, dissect the molecular mechanisms underlying anemia in MDS, and review therapeutic approaches to overcome ineffective erythropoiesis in patients with these diseases.
    SIGNIFICANCE: A better understanding of the biological mechanisms underlying anemia in MDS is needed to develop targeted therapies for a personalized treatment approach. Anemia, a hallmark of MDS, highly affects patients' quality of life and contributes to overall morbidity. Current knowledge of the mechanisms of action of the available drugs targeting anemia in MDS is limited.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-25-0393
  27. Proc Natl Acad Sci U S A. 2026 May 12. 123(19): e2604380123
    ATP2B1 expression identifies human hematopoietic stem cells with superior repopulation and self-renewal.
    Angelica Varesi, Murtaza S Nagree, Isabella Di Biasio, Andy G X Zeng, Sayyam Shah, Michael Zhang, Hyerin Kim, Alex Murison, Rohail Badami, Olga Gan, Liqing Jin, Jessica McLeod, Sheela A Abraham, Mark D Minden, Andrea Arruda, Igor Novitzky-Basso, Jonas Mattsson, John E Dick, Stephanie Z Xie.
      Long-term hematopoietic stem cells (LT-HSC) maintain lifelong hematopoiesis while preserving the stem cell compartment through self-renewal. The human LT-HSC compartment is molecularly and functionally heterogeneous and also varies across ontogeny. Dissecting the molecular basis for this variation is impeded by the paucity of immunophenotypic markers to resolve LT-HSC heterogeneity. Here, we identified ATPase plasma membrane calcium transporting 1 (ATP2B1/PMCA1) as a cell surface marker that is heterogeneously expressed by CD49f+ LT-HSC from fetal to adult hematopoiesis. ATP2B1 immunophenotypic expression stratified human CD49f+ LT-HSC from fetal liver, neonatal cord blood, and adult mobilized peripheral blood sources into functionally distinct subpopulations in single-cell (sc) clonogenic assays. CD49f+ATP2B1+ LT-HSC exhibited superior long-term repopulation and self-renewal capacities in vivo compared to CD49f+ATP2B1- LT-HSC. Molecular profiling by scMultiome and immunofluorescence microscopy point to enrichment of an HSC self-renewal program that includes the TFEB-endolysosomal axis in CD49f+ATP2B1+ LT-HSC. Our study provides a framework to dissect the heterogeneous molecular programs in LT-HSC.
    Keywords:  calcium; hematopoietic stem cell; lysosome
    DOI:  https://doi.org/10.1073/pnas.2604380123
  28. Haematologica. 2026 May 07.
    Venetoclax and gilteritinib combination for FLT3-mutated relapsed/refractory acute myeloid leukemia: a real-world single-center experience.
    Francesca Crupi, Gaia Ciolli, Matteo Piccini, Barbara Scappini, Laura Fasano, Elisa Quinti, Andrea Pasquini, Jessica Caroprese, Giacomo Gianfaldoni, Giovanna Motta, Raffaella Santi, Chiara Maccari, Paola Guglielmelli, Alessandro M Vannucchi, Francesco Mannelli.
      
    DOI:  https://doi.org/10.3324/haematol.2026.300692
  29. Cancer Discov. 2026 May 05.
    The evolution of polyclonal competition in aging hematopoiesis.
    Nathaniel V Mon Père, Francesco Terenzi, Benjamin Werner.
      Clonal hematopoiesis (CH) - the expansion of genetic variants in blood - is a prime example of somatic evolution. Although it often precedes malignant transformation, many aspects of this process remain unknown. We show that a model of polyclonal competition, in which selectively-advantaged clones continually appear and compete, explains observed CH dynamics throughout human life. We quantify the fitness distribution and occurrence rate of clonal expansions using either variant trajectories or HSC genetic heterogeneity. Inferences on both data converge. Approximately three fit clones enter the HSC pool per year, yet rarely more than five achieve >1.5% frequency throughout life. The fittest clones emerge predominantly later in life in accordance with a multistep evolutionary process. DNMT3A-variants were enriched for single-hit clones, whereas TET2, ASXL1, JAK2, SF3B1, and SRSF2 showed enrichment for multi-hit evolution. These findings suggest precursors of hematological malignancies are identifiable prior to transformation and may facilitate early intervention strategies.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-0990
  30. Blood. 2026 May 08. pii: blood.2025031474. [Epub ahead of print]
    Procr+ endothelial progenitor cells govern hematopoiesis through fine-tuning mesenchymal stem cell niche signals.
    Chang Xu, Xue Lv, Shangda Yang, Yanling Lv, Yawei Zheng, Yu-Xiang Wang, Yan Hui, Guohuan Sun, Xiangnan Zhao, Lan-Yue Ma, Honglin Duan, Linmin Zhang, Shuangshuang Pu, Lu Sun, Xialin Li, Yicheng He, Wenjia Fang, Meng Yang, Toshio Suda, Qi Chen, Tao Cheng, Hui Cheng.
      Hematopoietic stem cells (HSCs) rely on specialized niche cells for maintenance, yet how these regulators functionally integrate to preserve hematopoiesis remains unknown. Here, we identified a subset of Procr+ endothelial cells (ECs) with progenitor-like properties in bone marrow (BM), which is critical for vascular homeostasis and injury regeneration. Endothelial-specific ablation of Procr severely compromises BM vascular integrity and function. Beyond serving as a stem cell marker, Procr serves dual biological functions as a functional signaling receptor in multicellular communication. Mechanistically, Procr binds HSPA8 to promote Foxc2 nuclear translocation, upregulating Dll4 transcription to sustain Dll4/Notch3 activation in mesenchymal stem cells (MSCs), revealing a Procr/HSPA8/Foxc2/Dll4 axis essential for EC and MSC crosstalk. Through the HSPA8/Foxc2/Dll4/Notch3 axis, Procr+ ECs instruct MSCs Notch signaling, coordinating their adipogenic-osteogenic differentiation to maintain HSC self-renewal and myeloid output. Building on this mechanism, we demonstrated conserved functionality of Procr+ EPCs in human BM. Human PROCR+ ECs were found to similarly enhance DLL4/Notch3 signaling in MSCs, consequently preserving HSC function, confirming their therapeutic relevance. Our work highlights Procr⁺ EPCs sustain vascular integrity and govern MSC-dependent HSC maintenance, offering targeted clinical strategies for niche regeneration.
    DOI:  https://doi.org/10.1182/blood.2025031474
  31. Nat Cell Biol. 2026 May 04.
    NAT10 maintains stem cell homeostasis by mitigating mRNA decay through an ac4C-independent mechanism.
    Weiqian Li, Yue Huo, Zhaoru Zhang, Yiyang Liu, Xinyue Qian, Jia Ouyang, Rao Gu, Chenxi Han, Shuo Li, Rui Su, Jia Yu, Pengxu Qian, Fang Wang.
      Haematopoietic stem cells (HSCs) represent a well-established system for studying stem cell maintenance. While RNA regulators have been reported in HSCs, a systematic characterization and how they define transcript fate remains outstanding. Here we profile RNA characteristics of HSC-essential genes and uncover a notable feature in both human and mouse: they have extended 3' untranslated regions specifically enriched with AU-rich elements (AREs). These AREs are crucial for the expression of HSC genes, primarily through NAT10, which stabilizes their mRNAs. Notably, Nat10 deficiency markedly disrupts HSCs self-renewal and long-term reconstitution capacity. Mechanistically, NAT10 recruits ribosomes to the 3' untranslated region AREs of HSC-essential mRNAs, sheltering them from degradation-an effect independent of NAT10's ac4C catalytic activity. Moreover, NAT10 dysregulations were associated with multiple human haematological malignancies. Collectively, our findings uncover a specific mechanism of RNA turnover control mediated by specific RNA ARE motifs and identify a non-catalytic role of NAT10 in maintaining HSC homeostasis.
    DOI:  https://doi.org/10.1038/s41556-026-01949-1
  32. FEBS J. 2026 May 04.
    CDK14 is a critical regulator of haematopoietic stem and progenitor cell maintenance and post-transplantation proliferation.
    Ya-Fei Li, Tian-Jing Li, Yin Huang, Ke Bai, Rong-Rong Gao, Jia-Xin Yang, Lan-Yue Ma, Yan-Mei Yu, Jinjin Ma, Qi Chen, Yang Liu.
      Cyclin-dependent kinase (CDK) 14 is involved in Wnt signalling, tissue repair, and tumourigenesis, but its function in haematopoiesis remains unexplored. Here, we found that CDK14 was necessary to maintain physiological haematopoiesis under steady-state and haematopoietic reconstitution after transplantation using genetic and pharmacological interventions. By utilising Cdk14 knockout and haematopoietic-deletion (Cdk14∆HC) mouse models, in combination with the selective CDK14 inhibitor FMF-04-159-2, we showed that ablation of CDK14 resulted in diminished haematopoietic stem and progenitor cells (HSPCs), and disrupted the proportion of mature haematopoietic cells. Single-cell RNA sequencing analysis of bone marrow from Cdk14∆HC mice revealed impaired cell cycle progression, perturbed HSPC proportion, and altered niche-HSPC interactions. Furthermore, genetic and pharmacological ablation of CDK14 markedly decreased HSPC proliferation after transplantation in vivo and reduced colony formation in vitro. These findings identify CDK14 as a critical regulator of haematopoietic homeostasis and highlight its essential role in supporting HSPC function under stress conditions.
    Keywords:  cell cycle; cell interaction; haematopoiesis; haematopoietic stem and progenitor cell; microenvironment
    DOI:  https://doi.org/10.1111/febs.70562
  33. Blood. 2026 May 07. pii: blood.2025031836. [Epub ahead of print]
    Bone Marrow Stem Cell Connexins: Misconceptions and New Insights.
    Abhishek K Singh, Kathrine S Rallis, Jose A Cancelas.
      Hematopoietic regeneration requires coordinated activation of hematopoietic stem and progenitor cells (HSPCs) and adaptive remodeling of the bone marrow (BM) microenvironment to meet extreme metabolic and oxidative demands imposed by cytotoxic injury, transplantation, and inflammation. While soluble factors and cytokine signaling are central to this process, emerging evidence identifies direct intercellular communication as a critical regulatory layer in stress hematopoiesis. Connexins, particularly Connexin-43 (Cx43), form an evolutionarily conserved communication network that integrates metabolic coupling, redox buffering, and organelle dynamics across hematopoietic and stromal compartments. Beyond canonical gap junction channel activity, connexins exert non-junctional, compartment-specific functions through cytoplasmic, nuclear, and mitochondrial pools that regulate signaling scaffolds, transcriptional programs, cytoskeletal organization, mitochondrial dynamics, calcium homeostasis, and bioenergetics. In HSPCs, mitochondrial Cx43 functions as a metabolic checkpoint that preserves regenerative capacity by supporting oxidative phosphorylation, limiting chronic AMPK activation, maintaining fusion-fission balance, and preventing mitochondrial Ca²⁺ overload. In parallel, Cx43 enables mitochondrial transfer from donor HSPCs to stromal niche cells, restoring stromal metabolic competence and promoting effective niche repair and engraftment. Dysregulation of connexin networks contributes to marrow failure, clonal evolution, leukemic niche remodeling, and chemoresistance, highlighting their context-dependent roles in health and disease. This review synthesizes advances in connexin biology in hematopoiesis, reframes connexins as integrators of metabolic and regenerative signaling rather than passive conduits, and defines emerging translational opportunities. Isoform- and compartment-specific targeting of connexin pathways offers a therapeutic strategy to enhance hematopoietic recovery, preserve long-term stem cell function, and disrupt pathological niche support in hematologic malignancies.
    DOI:  https://doi.org/10.1182/blood.2025031836
  34. Haematologica. 2026 May 07.
    Pediatric blastic plasmacytoid dendritic cell neoplasms are molecularly defined by recurrent MYB rearrangements: clinical and molecular insights.
    Mahsa Khanlari, Marleni Torres Nunez, Jamie L Maciaszek, Mohammad K Eldomery, Wei Wang, Zhongshan Cheng, Jason Myers, Karissa Dieseldorff Jones, Gabriela Gheorghe, Laura Key, Yen-Chun Liu, Rafael Barceiro, Armando Peña, Sharon Castellino, Roy Enrique Rosado, Marcela Barros E Sousa, Jacob R Bledsoe, Naveen Pemmaraju, Jeffery M Klco, Raul C Ribeiro.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2026.300903
  35. Blood. 2026 Apr 04. pii: blood.2024028189. [Epub ahead of print]
    The Evolution of Haematopoietic Models Through a Clonal Lens.
    Sara Tomei, Tom S Weber, Shalin H Naik.
      Haematopoiesis is a tightly regulated process through which a small pool of stem cells sustains the lifelong production of all blood cell types in response to physiological demand. Understanding how this process is controlled, and how haematopoietic stem cells (HSCs) commit to specific lineages, is essential to fine tune immune cell production both in vivo and in vitro for cell therapy applications. In this review, we examine the major conceptual frameworks that have been proposed to describe haematopoiesis and the underlying data that informed them, ranging from the classical discrete hierarchy to the continuous model, the punctuated continuum, and the multi-track model. Evidence from clonal lineage-tracing studies in mouse, non-human primates, and humans supports the idea that lineage fate is largely predetermined rather than stochastically acquired, and we highlight the importance of clonal multi-omics approaches for identifying the molecular predictors of fate. We then discuss the computational models that have been developed to study haematopoietic development. Finally, we outline key challenges, including resolving native haematopoiesis in vivo, in both mouse and humans, and identifying the molecular programs that encode fate trajectories and how they are altered in disease. Looking at the haematopoietic process through a clonal lens is paramount to find the molecular signatures that truly can predict fate.
    DOI:  https://doi.org/10.1182/blood.2024028189
  36. Nat Genet. 2026 May 05.
    Age distinguishes selection from causation in cancer genomes.
    David Cheek, Martin Blohmer, Martin A Nowak, Tibor Antal, Kamila Naxerova.
      Cancer-causing mutations have been identified primarily from positive selection signals in cancer genomes. However, positive selection is also a ubiquitous feature of normal tissue aging. Here we develop a statistical framework to disentangle selection in normal tissue and causation of carcinogenesis. By comparing cancer and normal tissue genomes, we estimate the effects of mutations on cancer risk in the blood, esophagus and colon. We determine that stronger cancer-causing mutations are enriched at younger patient ages. This enables cancer-causing mutations to be identified from patient age distributions, even without normal tissue data. Moreover, we show for acute myeloid leukemia that the age-dependence of purported causal mutations can be explained largely by normal blood evolution, challenging the long-standing notion that childhood cancers require distinct mutations. Broadly, our framework delineates carcinogenesis from normal tissue aging, improving the assessment of cancer risk conferred by mutations.
    DOI:  https://doi.org/10.1038/s41588-026-02593-z
  37. Blood Cancer J. 2026 May 07. pii: 70. [Epub ahead of print]16(1):
    Impact of thrombosis on disease progression, cancer and mortality in patients with essential thrombocythemia and polycythemia vera.
    A Angona, B Cuevas, M Pérez-Encinas, F Ferrer-Marin, A Senín, E Arellano-Rodrigo, J C Hernández-Boluda, M I Mata Vázquez, G Caballero-Navarro, M T Gómez-Casares, E Magro, G Carreño-Tarragona, M A Cortés-Vázquez, R Pérez López, V García-Gutiérrez, M S Noya-Pereira, J M Alonso-Dominguez, C Sierra-Aisa, L Fox, C García Hernández, J M Guerra, E Cerezo, M Gasior, M Santaliestra, I Díez, M V Cuevas, L Sanz, I Pastor, R Stuckey, P Vélez, C Auría-Caballero, A Alvarez-Larrán.
      
    DOI:  https://doi.org/10.1038/s41408-026-01513-y
  38. Bone Marrow Transplant. 2026 May 04.
    Impact of donor and recipient EBV serostatus on transplant outcomes in patients with acute leukemia after haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide: Infectious Diseases Working Party EBMT retrospective study.
    Jan Styczynski, Gloria Tridello, Inge Verheggen, Nina Knelange, Lotus Wendel, Per Ljungman, Jose Luis Piñana, Malgorzata Mikulska, Lidia Gil, Simone Cesaro, Fabio Ciceri, Raffaella Greco, Depei Wu, Didier Blaise, Raffaella Cerretti, Patrice Chevallier, Edouard Forcade, Flore Sicre de Fontbrune, Mohamad Mohty, Sophie Ducastelle Lepretre, Claude Eric Bulabois, Stephanie Nguyen Quoc, Ibrahim Yakoub-Agha, Rafael de la Camara, Dina Averbuch.
      
    DOI:  https://doi.org/10.1038/s41409-026-02898-x
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