bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2026–04–26
thirty papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. HDAC8 inhibition targets STAT3-MYC axis and synergizes with Venetoclax in KMT2A-rearranged acute myeloid leukemia.
  2. Results of a phase 1 trial testing ruxolitinib plus venetoclax in patients with relapsed/refractory acute myeloid leukemia.
  3. Imputing causality and clonal dynamics from single-cell transcriptomics in paroxysmal nocturnal hemoglobinuria.
  4. Stem11 score: towards rapid clinical prognostication for acute myeloid leukemia.
  5. Single cell transcriptional evolution of myeloid leukemia of Down syndrome.
  6. Physiological MplW514L expression in hematopoietic stem cell causes an essential thrombocythemia and progressive myelofibrosis.
  7. MYST acetyltransferases interact with SETBP1 and are a targetable therapeutic vulnerability in SETBP1-mutant leukemia.
  8. Longitudinal localization of leukaemic stem cells between the metaphysis and central marrow governs their behaviour.
  9. ASC4OPT: asciminib treatment optimization study in patients with chronic myeloid leukemia in chronic phase previously treated with two or more tyrosine kinase inhibitors.
  10. Real-World Outcomes of FLAG-Ida Regimen in 1079 Adult Patients With First Relapsed/Refractory AML: A PETHEMA Study.
  11. Genomic evolution and natural history of myeloproliferative neoplasms on therapy.
  12. IFNγ Drives Long-Term Bone Marrow Niche Dysfunction Following Doxorubicin-Based Chemotherapy.
  13. Surface CD81 supports leukemia stem cell function and reveals a therapeutic vulnerability in acute myeloid leukemia.
  14. Outcomes of 544 Patients with t(6;9)/DEK::NUP214 acute myeloid leukemia undergoing allogeneic stem cell transplantation: an EBMT study on behalf of the acute leukemia working party (ALWP) and the pediatric diseases working party (PDWP).
  15. Recovering from a therapeutic stall in higher-risk myelodysplastic syndromes: re-examining biology, backbones and study designs.
  16. TOE1 is a β-catenin interacting protein regulating the proliferation of hematopoietic cells through PAK2 modulation.
  17. Roles of RRM2 and RRM2B in pyrimidine stress responses and differentiation of acute myeloid leukemia cells.
  18. MMRN1-EGFR drives sialylglycan-Siglec immune evasion in AML leukemia stem cells.
  19. Pharmacological boosting of azacitidine/venetoclax in acute myeloid leukemia.
  20. Debio 1562M CD37-targeting ADC is highly active and well tolerated in preclinical models of AML and MDS.
  21. Outstanding Questions to Understand and Target Splicing Factor-Mutant Blood Cancers.
  22. APL-like subset within NPM1-mutated AML: A distinct immunophenotype correlating with early vascular complications.
  23. Recombinant zoster vaccine induces superior immunogenicity compared with live varicella vaccine in allogeneic haematopoietic stem cell transplantation recipients.
  24. Suppression of UCP2 alleviates leukemogenesis by enhancing branched-chain amino acids-induced oxidative stress via activating the PI3K/AKT/mTOR signaling pathway.
  25. Novel KAT6B::NUTM2B fusion oncogene in congenital acute myeloid leukemia and implications for menin inhibitor therapy.
  26. The Clinicopathologic and Genomic Features of Mature Versus Blastic Plasmacytoid Dendritic Cell Neoplasms Arising From Chronic Myeloid Neoplasms.
  27. Phase I/II Trial of the FLT3 Kinase Inhibitor XY0206 in Patients With Relapsed/Refractory Acute Myeloid Leukemia.
  28. XPO1 inhibitor selinexor suppresses homologous recombination by inhibiting E2F7 nuclear export in acute myeloid leukemia.
  29. Extended HLA Haplotypes and Transplant Survival.
  30. MBP1 inhibits AML proliferation through downregulating noncanonical Wnt/Ca2+ signaling pathway.
  1. Leukemia. 2026 Apr 21.
    HDAC8 inhibition targets STAT3-MYC axis and synergizes with Venetoclax in KMT2A-rearranged acute myeloid leukemia.
    Lianjun Zhang, Wancheng Guo, Yu-Hsuan Fu, Dijiong Wu, Man Li, Ying-Chieh Chen, Chi-Yang Tseng, Wei-Kai Hua, Le Xuan Truong Nguyen, Xin He, Haojie Dong, Lei Zhang, Bin Zhang, Ling Li, Guido Marcucci, Ya-Huei Kuo.
      KMT2A-rearranged (KMT2A-r) acute myeloid leukemia (AML) is an aggressive AML subtype characterized by 11q23 chromosomal rearrangements involving KMT2A gene and clinically associated with poor prognosis. Herein, we show that HDAC8 is upregulated in KMT2A-r AML and high HDAC8 is associated with poor overall survival in KMT2A-r AML patients. Using a KMT2A::MLLT3 mouse model, we demonstrate that both genetic knockout and pharmacological inhibition of HDAC8 significantly delayed leukemia progression, prolonged survival and reduced disease recurrence. Mechanistically, HDAC8 inhibition downregulates STAT3-MYC axis independent of TP53 status across AML genetic subtypes. Biochemical assays revealed that HDAC8 binds directly to STAT3, promoting its deacetylation and stabilization, while HDAC8-selective inhibitor (HDAC8i) treatment results in increased STAT3 acetylation and subsequent STAT3 degradation which in turn downregulates MYC. Given that STAT3-MYC signaling promotes cell survival and Venetoclax resistance, we show that HDAC8i exhibits synergistic anti-leukemia activity with Venetoclax in primary AML cells regardless of TP53 status. Combination of HDAC8i and Venetoclax synergistically reduced leukemia burden and significantly prolonged survival in both KMT2A::MLLT3 AML and patient-derived xenograft models. This study highlights the regulatory function of HDAC8 on STAT3-MYC and provides the proof-of-principle for targeting HDAC8 in combination with Venetoclax for the treatment of KMT2A-r AML.
    DOI:  https://doi.org/10.1038/s41375-026-02950-1
  2. Blood Neoplasia. 2026 May;3(2): 100205
    Results of a phase 1 trial testing ruxolitinib plus venetoclax in patients with relapsed/refractory acute myeloid leukemia.
    Uma Borate, Cristina E Tognon, Yazan F Madanat, Shikha Misra, Andy Kaempf, Prapti A Patel, Kara L Davis, Junwei Sun, Lucille Stuani, Eric D Eisenmann, Christopher A Eide, Stephen E Kurtz, Kevin Watanabe-Smith, Kara Johnson, Astraea Jager, Stein-Erik Gullaksen, Bridget Robinson, Tania Vu, Sylvia K Plevritis, Sharyn D Baker, Jessica Minnier, Peter Clement, Sammantha Avaylon, Madison Hayes, Laura F Newell, Arpita P Gandhi, Jessica Leonard, Brandon Hayes-Lattin, Sumithira Vasu, Rachel J Cook, Gabrielle Meyers, Richard T Maziarz, Elie Traer, Ronan Swords, Jeffrey W Tyner, Brian J Druker, Jennifer N Saultz.
      Functional small-molecule screening of primary acute myeloid leukemia (AML) samples identified ex vivo synergy between the JAK1/2 inhibitor, ruxolitinib (Rux), and venetoclax (Ven) in newly diagnosed and relapsed/refractory (R/R) AML. This motivated a phase 1 multicenter trial to evaluate Rux + Ven in 30 patients with R/R AML. Patients had median age of 69 years and were heavily pretreated (40% with ≥3 previous lines, 43% with previous Ven failure). Rux (30 mg twice daily) and Ven (400 mg once daily) were well tolerated without dose-limiting toxicities. Median duration of therapy was 55 days. Over 2 cycles of Rux + Ven, clinical response rate was 20% and composite complete remission (CR) rate was 10%. Median survival was 3.7 months, with 23% alive at 1 year. There were 2 exceptional responders, including a patient who remained in CR/CR with incomplete hematologic recovery for nearly 4 years after hypomethylating agent + Ven failure. CD56 expression on blasts was significantly associated with lack of clinical response (odds ratio, 0.09; P = .039) and shorter survival (hazard ratio, 2.35; P = .048). In a subset of patients (n = 8), cytometry by time of flight comparison of primary cells at pretreatment vs day 8 showed upregulation of pCREB and downregulation of CD11b in nonresponders. In summary, the novel combination of Rux + Ven is safe in adult patients with R/R AML. Our study identified cellular and molecular biomarkers, notably CD56, that predict resistance to Rux + Ven, but further work is needed to understand and validate their effect in AML. This trial was registered at www.clinicaltrials.gov as #NCT03874052.
    DOI:  https://doi.org/10.1016/j.bneo.2026.100205
  3. Leukemia. 2026 Apr 22.
    Imputing causality and clonal dynamics from single-cell transcriptomics in paroxysmal nocturnal hemoglobinuria.
    Hiroki Mizumaki, Shouguo Gao, Zhijie Wu, Fernanda Gutierrez-Rodrigues, Lemlem Alemu, Diego Quinones Raffo, Ivana Darden, Olga Rios, Jennifer Lotter, Sachiko Kajigaya, Jibran Durrani, Emma M Groarke, Bhavisha A Patel, Neal S Young.
      Paroxysmal nocturnal hemoglobinuria (PNH) originates from hematopoietic stem cells (HSCs) harboring somatic mutations in the phosphatidylinositol glycan class A (PIGA) gene. Clonal expansion of PIGA-mutated cells occurs uniquely in the setting of bone marrow (BM) failure, but specific pathophysiologic mechanisms remain unclear. We performed single-cell RNA sequencing (scRNA-seq) of BM cells from patients with large (> 50%) and small (10-50%) PNH cell fractions. In patients with large PNH cell fractions, phenotypically normal hematopoietic stem and progenitor cells (HSPCs) upregulated immune response and apoptosis pathways and downregulated cell-cycling pathways compared with PNH-type HSPCs. BM effector cells upregulated immune response pathways, and cell-cell communication between effector cells and normal HSPCs was greater than in controls. In contrast, in patients with small PNH cell fractions, transcriptional changes in normal HSPCs were reversed: downregulation of immune response pathways and upregulation of the cell-cycling pathways. Notably, transcriptional differences associated with PNH cell fractions were primarily in normal HSCs, whereas PNH-type HSCs showed similar transcriptional profiles between patients with large and small PNH cell fractions. These results implicate immunological negative selection against normal HSCs in PNH. Error-corrected DNA sequencing of patients' blood samples identified multiple PIGA mutations in each patient, consistent with strong selection for the resulting phenotype.
    DOI:  https://doi.org/10.1038/s41375-026-02914-5
  4. Exp Hematol. 2026 Apr 17. pii: S0301-472X(26)00074-3. [Epub ahead of print] 105441
    Stem11 score: towards rapid clinical prognostication for acute myeloid leukemia.
    Tomoya Isobe, Manja Meggendorfer, Sebastian Wolf, Thomas Oellerich, Nicola K Wilson, Berthold Göttgens.
      Acute myeloid leukemia (AML) is an aggressive form of myeloid malignancy with high relapse and poor survival rates. Despite recent advances in genomics-based risk classification, accurate prediction of patient outcomes remains a challenge, posing the need for complementary molecular information to enable precise treatment stratification. In the current study, we assess the prognostic value of the recently developed 11-gene Stem11 signature in a uniformly treated cohort of 107 de novo AML patients and show that Stem11 classification stratifies overall survival and response to allogeneic hematopoietic cell transplantation across the European LeukemiaNet risk groups. We further develop a NanoString-based Stem11 scoring platform and validate its high concordance with RNA-sequencing-based scoring and its retained prognostic power to identify the most refractory AML subgroup. With its rapid turnaround time and standardized built-in analysis pipeline, our NanoString-based Stem11 scoring panel represents a faster yet reliable alternative to RNA-sequencing, providing preclinical proof of concept for Stem11-based clinical decision support. TEASER ABSTRACT: Acute myeloid leukemia (AML) is an aggressive hematological malignancy with poor prognosis. Current genetic risk stratification remains insufficient for accurately predicting patient outcomes, and additional information that can refine and improve prospective risk prediction is urgently needed. Here, we develop a NanoString-based diagnostic assay measuring the prognostic Stem11 score. Our assay provides highly concordant Stem11 scores with RNA-sequencing-based quantification, thereby establishing a rapid and reliable transcriptional prognostication system for time-sensitive clinical decision support for AML.
    Keywords:  Gene expression; NanoString; Prognostication; acute myeloid leukemia
    DOI:  https://doi.org/10.1016/j.exphem.2026.105441
  5. Nat Commun. 2026 Apr 23. pii: 3474. [Epub ahead of print]17(1):
    Single cell transcriptional evolution of myeloid leukemia of Down syndrome.
    Mi K Trinh, Konstantin Schuschel, Hasan Issa, Rebecca Thomas, Conor Parks, Agnes Oszlanczi, Toochi Ogbonnah, Di Zhou, Lira Mamanova, Elena Prigmore, Emilia R Robertson, Angus Hodder, Anna Wenger, Nathaniel D Anderson, Holly J Whitfield, Taryn D Treger, José Gonçalves-Dias, Karin Straathof, David O'Connor, Matthew D Young, Laura Jardine, Stuart Adams, Jan-Henning Klusmann, Jack Bartram, Sam Behjati.
      Children with Down syndrome have a 150-fold increased risk of developing myeloid leukaemia (ML-DS). Unusually for a childhood leukaemia, ML-DS arises from a preleukaemic state, termed transient abnormal myelopoiesis (TAM), via a conserved sequence of mutations. Here, we examine the relationship between the genetic and transcriptional evolution of ML-DS from natural variation; a rich collection of primary patient samples and foetal tissues with a range of constitutional karyotypes. We distil transcriptional consequences of each genetic step in ML-DS evolution, utilising single-cell mRNA sequencing, complemented by phylogenetic analyses in progressive disease. We find that transcriptional changes induced by the TAM-defining GATA1 mutations are retained in, and account for most of the ML-DS transcriptome. The GATA1 transcriptome pervades all stages of ML-DS, including progressive disease that had undergone genetic evolution. Our approach delineates the transcriptional evolution of ML-DS and provides an analytical blueprint for distiling consequences of mutations within their pathophysiological context.
    DOI:  https://doi.org/10.1038/s41467-026-71707-2
  6. J Clin Invest. 2026 Apr 23. pii: e199690. [Epub ahead of print]
    Physiological MplW514L expression in hematopoietic stem cell causes an essential thrombocythemia and progressive myelofibrosis.
    Shujing Zhang, Jingjing Liu, Yuan Li, Yi Wang, Lingling Wang, Miaomiao Xu, Yanxia Li, Ge Dong, Shanshan Wang, Yanmei Li, Zhigang Cai, Baobing Zhao.
      Typ515 (W515) mutations in the protein MPL are one of key driver mutations promoting BCR/ABL-negative myeloproliferative neoplasms (MPNs), but their effects on hematopoietic stem cells (HSCs) and MPN-related hematological abnormalities have not been studied in physiological contexts. Here, we established a MplW514L knock-in mouse model which largely mimics human MPLW515L mutation during hematopoiesis. The mutant mice developed an essential thrombocythemia (ET)-like MPN phenotypes, displaying excess megakaryopoiesis and thrombocytosis and progressive myelofibrosis. Mechanistically we observed that MplW514L-conditioned HSC compartment had a unique disease-initiating capacity however it did not exhibit a obvious advantage of competitive repopulation over wild-type control. Notably, single-cell analysis and flow cytometry profiles support that MplW514L expression led to a significant expansion of megakaryocyte-biased stem cell fate within the HSC pool. Finally, JAK2 inhibitor treatment phenotypically alleviated the ET signs but failed to eliminate the disease-initiating HSCs. These findings underscore the etiology of physiological expression of MPLW515L mutation in HSCs, and also provide a valuable in vivo model to evaluate potential therapeutic options for patients with MPLW515L-positive MPN.
    Keywords:  Hematology; Hematopoietic stem cells; Leukemias; Mouse models; Oncology
    DOI:  https://doi.org/10.1172/JCI199690
  7. Blood Cancer Discov. 2026 Apr 19.
    MYST acetyltransferases interact with SETBP1 and are a targetable therapeutic vulnerability in SETBP1-mutant leukemia.
    Hanqian L Carlson, Thai T Nguyen, Samantha Tauchmann, Sarah A Carratt, Traci L Kruer, Nana Adjoa Dankyi, Maria E Balasis, Hyeyoon Kim, Chia-Feng Tsai, Tao Liu, Shawn B Shrestha, Jared M Fischer, Eric Padron, Theodore P Braun, Julia E Maxson.
      Mutations in SETBP1 are associated with adverse prognosis in myeloid malignancies. These mutations stabilize SETBP1 protein, driving increased expression of a progenitor-associated gene expression program through incompletely described mechanisms. A proteomic screen revealed interactions between SETBP1 and MYST acetyltransferase complexes, including the catalytic subunits-KAT6A and KAT7. In cell line and primary hematopoietic models, mutant SETBP1 increased the localization of MYST complexes at known SETBP1 target genes, including the HOXA cluster, where they were shown to drive increased histone acetylation and gene expression. Treatment of SETBP1D868N-expressing myeloid progenitors with MYST inhibitors reduced target gene expression. To establish the efficacy of MYST inhibition in vivo, we treated mice harboring a syngeneic SETBP1-mutant leukemia with the clinical-grade MYST inhibitor-PF-9363. This resulted in hematologic control and increased survival. MYST inhibition was also highly effective against a SETBP1-mutant PDX model. These studies identify MYST acetyltransferases as promising therapeutic targets in SETBP1-mutant malignancies.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-25-0446
  8. Nat Cell Biol. 2026 Apr 24.
    Longitudinal localization of leukaemic stem cells between the metaphysis and central marrow governs their behaviour.
    Chen Wang, Yi Pan, Ruochen Dong, Wenxuan Zhou, Xiaduo Meng, Xi Kang, Ravi Nistala, Richard D Hammer, Linheng Li, XunLei Kang.
      Leukaemic stem cells (LSCs) reside in protective bone marrow (BM) niches that promote therapeutic resistance and relapse. Here we characterized longitudinal BM niches supporting LSC survival, distinguishing the metaphysis from the central marrow. Quiescent LSCs preferentially localized to the metaphysis and exhibited reduced stemness and aggressiveness upon mobilization to the central marrow. Targeting DPP4 in acute myeloid leukaemia (AML) cells altered CXCL12 gradients at three spatial scales. Systemically, reversal of the BM-peripheral blood CXCL12 gradient confined AML cells within the BM. At the BM level, disruption of the metaphysis-central marrow gradient displaced LSCs from their protective niche. At the microscale, loss of the CXCL12 gradient between N-cadherin+ stromal cells and the surrounding matrix impaired LSC recruitment. These effects arise from the CXCL12-DPP4-GPC3 axis, in which DPP4 truncates and inactivates CXCL12, whereas stromal GPC3 restrains DPP4 activity. Modulating this axis disrupts niche protection and enhances therapeutic vulnerability in AML.
    DOI:  https://doi.org/10.1038/s41556-026-01939-3
  9. Leukemia. 2026 Apr 23.
    ASC4OPT: asciminib treatment optimization study in patients with chronic myeloid leukemia in chronic phase previously treated with two or more tyrosine kinase inhibitors.
    Andreas Hochhaus, Philipp le Coutre, Dragana Milojkovic, Dennis Dong Hwan Kim, Soo Min Lim, Carolina Pavlovsky, Thanh Nguyen, Franck Emmanuel Nicolini, Beatriz Moiraghi, Sebastian Grosicki, Chi Dung Phu, Gabriel Etienne, Fernando Marco de Lucas, Rosa Maria Ayala Diaz, Massimo Breccia, Charles Chuah, Roberto Abi Rached, Himanshu Pokhriyal, Aswin Ic, Peter Schuld, Virginia Pilipovic, Franz Alisch, Carla Maria Boquimpani.
      The ASC4OPT non-comparative phase 3b study (NCT04948333) evaluates asciminib once daily (QD) or twice daily (BID) in chronic myeloid leukemia in chronic phase (CML-CP) treated with ≥2 tyrosine kinase inhibitors (TKIs). This study enrolled 169 patients not in major molecular response (MMR), with unsatisfactory response (intolerant, warning or failure) as defined by European LeukemiaNet (ELN) 2020 criteria. Patients intolerant to their most recent TKI and in MMR at baseline (n = 30) were also enrolled. The primary endpoint was the MMR rate at Week 48 for patients not in MMR at baseline. Results showed an overall MMR rate of 39.4% at Week 48 (40 mg BID, 43.4%; 80 mg QD, 35.4%) and 43.6% at Week 96 (40 mg BID, 45.8%; 80 mg QD, 41.5%) in patients not in MMR at baseline. Among 40 patients who had their asciminib dose escalated to 200 mg QD, 17.5% were in MMR at Week 96. Most patients in MMR at baseline remained in MMR at 48 and 96 weeks (93.3% and 86.7%, respectively). Safety for both dosing regimens was consistent with that of previous studies. Findings support asciminib as a potential standard of care for patients with CML-CP who have not responded optimally to prior TKI therapy.
    DOI:  https://doi.org/10.1038/s41375-026-02965-8
  10. Am J Hematol. 2026 Apr 22.
    Real-World Outcomes of FLAG-Ida Regimen in 1079 Adult Patients With First Relapsed/Refractory AML: A PETHEMA Study.
    Gaspar Aspas Requena, Rebeca Rodríguez-Veiga, Cristina Gil, Carmen Botella, Eliana Aguiar, Fernanda Trigo, Mercedes Colorado, Teresa Del Bernal Del Castillo, Eva Barragan, Mar Tormo, Eduardo Rodríguez Arbolí, Josefina Serrano López, Raimundo García Boyero, Tamara Castaño, Pilar Herrera Puente, Mónica A Romero Riquelme, María J Sayas Lloris, Lorenzo Algarra-Algarra, Carlos Rodriguez-Medina, Claudia L Sossa Melo, Jorge Labrador Gomez, Susana Vives, Olga Salamero, María Luz Amigo, Marta Valero Nuñez, Christine Rojas, Francisca Bass, María García-Fortes, Belén Vidriales Vicente, Marta Polo, Celina Benavente, María D Madrigal, Marcela Espinoza, Manuel Pérez-Encinas, María L Amador Barciela, Guiomar Bautista, Antonio Solana-Altabella, Isabel Cano-Ferri, Rafael Colmenares, Patricia García-Ramírez, Francisco Ibáñez Alis, Manuel Barrios García, Gabriela Rodríguez-Macías, Miguel López, Ana Yurena Oliva Hernández, Carlos Javier Cerveró, David Martínez-Cuadrón, Pedro Chorão, Juan M Bergua Burgues, Pau Montesinos.
      In a large multicenter real-world cohort, we aimed to evaluate outcomes of FLAG-Ida salvage therapy for relapsed/refractory (R/R) acute myeloid leukemia (AML) and validated the SALFLAGE prognostic score. We analyzed 1079 adults with R/R AML treated across 112 PETHEMA institutions over 26 years (1998-2024), including patients with primary refractory disease (36.9%) and first relapse episode (63.1%), with a median age of 52 years. Complete remission composite (CRc) was achieved 56.8%, including complete remission (CR) in 51.0%, CR with incomplete recovery in 4.0%, and morphological-free-state in 1.8%, enabling 35.2% of patients and 62% of responders to proceed to allogeneic transplantation without morphological disease. With median follow-up of 50.9 months, median overall survival (OS) was 10.2 months, with 5-year OS rate of 21.6%. Prior allogeneic transplantation (HR 0.54; p < 0.001) and relapse-free interval ≥ 1 year (HR 0.75; p = 0.024) independently predicted improved OS, whereas modified high-risk cytogenetics including t(8; 21) (HR 3.58; p < 0.001), FLT3-ITD mutation at primary diagnosis (HR 1.61; p < 0.001), and age ≥ 60 (HR 1.43; p < 0.001) conferred inferior OS. Validation of the SALFLAGE score demonstrated moderate discrimination (C-index 0.67), with 5-year survival of 38.4%, 27.2%, and 12.7% across risk categories (p < 0.001). Outcomes improved over periods (1998-2005 vs. 2006-2016 vs. 2017-2024): 30-day mortality was 6.9% vs. 9.3% vs. 5.0%, respectively (p = 0.030), and median OS was 7.8 versus 9.4 versus 11.1 months, respectively (p = 0.16). We confirm FLAG-Ida as a reference salvage regimen in fit R/R AML and validate the SALFLAGE score in this setting.
    Keywords:  FLAG‐Ida; acute myeloid leukemia; real‐world; relapsed/refractory; salvage therapy
    DOI:  https://doi.org/10.1002/ajh.70340
  11. Cancer Discov. 2026 Apr 20.
    Genomic evolution and natural history of myeloproliferative neoplasms on therapy.
    Daniel Leongamornlert, Joe Lee, Aleksandra E Kamizela, Ken To, Daniel Myers, Nicholas Williams, Kudzai Nyamondo, Xin Wang, Jing Guo, Ruchira K Dissanayake, Jane Price, Amer J Durrani, Jonathan Lambert, Michael Spencer Chapman, John E Pimanda, E Joanna Baxter, Anthony R Green, Anna L Godfrey, Jyoti Nangalia.
      Philadelphia-negative myeloproliferative neoplasms are chronic blood neoplasms. Treatments control blood counts but disease can progress to myelofibrosis or acute myeloid leukaemia. We performed longitudinal whole-genome and targeted sequencing in 30 patients, integrating clonal dynamics with 7,986 blood counts and clinical histories. Distinct evolutionary patterns distinguished stable from progressive disease, with leukaemic transformation arising via TP53 loss, stepwise driver mutation acquisition within complex clones, or emergence of independent leukaemic clones. In contrast, stable disease showed long-term clonal equilibrium without new drivers. Phylogenetic analysis using 203 whole-genomes of haematopoietic colonies revealed age-appropriate polyclonal haematopoiesis in triple-negative essential thrombocythaemia and germline predisposition to thrombocytosis, supporting non-neoplastic origins. Therapy-associated mutagenesis was observed, including C>G mutations following azacitidine and characteristic T>A/T>G after hydroxycarbamide exposure in blood cells, although not in skin where UV damage predominated. These findings demonstrate progression is genomically encoded years in advance and support serial monitoring and further study of treatment-related mutagenesis.
    DOI:  https://doi.org/10.1158/2159-8290.CD-26-0410
  12. Blood. 2026 Apr 20. pii: blood.2025030946. [Epub ahead of print]
    IFNγ Drives Long-Term Bone Marrow Niche Dysfunction Following Doxorubicin-Based Chemotherapy.
    Ximing Li, Alicia G Aguilar-Navarro, Mursal Nader, Soheil Jahangiri, Ho Seok Lee, Gibran Edun, Mark Gower, Dustin Yang, Minerva Fernandez, Brian Lin, Donghun Oh, Stephanie Farhat, David-Michael Phillips, Samantha Bartman, David Iain Murray, Christina Marie Kaszuba, Pathum Kossinna, Manjula Kamath, Cari Whyne, Gregory Schwartz, Jeevisha Bajaj, Thomas Kislinger, Bo O Zhou, Daniel L Coutu, Margarete K Akens, Adele Changoor, Thierry Mallevaey, Federico Gaiti, Courtney L Jones, Shruti Naik, Mark D Minden, Andrea Arruda, Johann K Hitzler, Ki Jun Lee, Yong-Mi Kim, Ralf H Adams, Kishor K Sivaraj, Anastasia N Tikhonova.
      Cancer survivors experience long-term skeletal and hematopoietic complications that limit quality of life following chemotherapy (CTX), yet the mechanisms underlying these defects remain incompletely understood. Using a murine model of doxorubicin (DOX)-based leukemia induction therapy, we show that CTX induces inflammatory remodeling of the bone marrow (BM) niche. DOX treatment resulted in loss of arteriolar vasculature, blockade of mesenchymal stromal cell (MSC) differentiation, trabecular bone loss, and reduced niche capacity to maintain hematopoietic stem cells (HSCs). These defects were accompanied by aberrant immune activation within the BM, marked by increased interferon-γ (IFNγ) production by CD8⁺ T cells. Inhibition of IFNγ signaling partially restored arteriolar vessels and adipogenic differentiation. Moreover, combined IFNγ blockade and deferoxamine mesylate (DFM), which promotes vascular recovery, attenuated chemotherapy-associated skeletal damage. Consistent with these findings, paired BM samples collected at diagnosis and post-CTX from leukemia patients exhibited altered MSC lineage priming, upregulation of inflammatory pathways, and expansion of BM CD8⁺ memory T cells after treatment. Together, these findings implicate IFNγ-driven chronic inflammatory remodeling as a central mechanism of CTX-associated BM niche dysfunction and pinpoints inflammatory signaling as a potential target to preserve BM function and long-term tissue integrity.
    DOI:  https://doi.org/10.1182/blood.2025030946
  13. Signal Transduct Target Ther. 2026 Apr 21. pii: 145. [Epub ahead of print]11(1):
    Surface CD81 supports leukemia stem cell function and reveals a therapeutic vulnerability in acute myeloid leukemia.
    Fanny Gonzales, Pauline Peyrouze, Djohana Laurent, Thomas Boyer, Nihad Boukrout, Cyril Couturier, Soizic Houdiard, Véronique Lisi, Adeline Barthélémy, François Sevrin, Adriana Plesa, Antonino Bongiovanni, Nicolas Pottier, Claude Preudhomme, Vincent-Philippe Lavallée, Konstantinos Geles, Nicolas Duployez, Céline Berthon, Christophe Roumier, Meyling Cheok.
      Relapse remains the leading cause of mortality in acute myeloid leukemia (AML), largely due to the persistence of therapy-resistant leukemia stem cells (LSCs). However, surface determinants that sustain LSC function and disease aggressiveness remain incompletely defined. Here, we identify the tetraspanin CD81 as a regulator of LSC function, progression and treatment resistance in AML. Analysis of retrospective patient cohorts revealed that high CD81 surface expression is associated with relapse and adverse clinical outcomes in non-core-binding factor AML. Functional studies demonstrated that elevated CD81 expression promotes chemoresistance and enhances leukemic engraftment in immunodeficient mouse models. In vivo gain- and loss-of-function approaches further established that CD81 drives increased leukemia burden and aggressive disease behavior. Notably, CD81 was enriched within LSC-containing subpopulations, where its expression supported LSC maintenance and resistance to chemotherapy. Mechanistically, CD81 promotes chemoresistance and leukemic aggressiveness through pathways linked to LAPTM4B-mediated STAT3 signaling and enhanced adhesion-dependent cellular interactions. These effects were accompanied by increased migration, invasion, and formation of filopodia-like membrane protrusions. Importantly, therapeutic immunotargeting of CD81 significantly reduced leukemic burden while exhibiting a manageable toxicity profile in preclinical models. Collectively, these findings establish CD81 as a clinically relevant surface marker associated with AML relapse and identify CD81-dependent signaling as a therapeutic vulnerability for targeting LSCs and preventing disease recurrence.
    DOI:  https://doi.org/10.1038/s41392-026-02697-2
  14. Bone Marrow Transplant. 2026 Apr 22.
    Outcomes of 544 Patients with t(6;9)/DEK::NUP214 acute myeloid leukemia undergoing allogeneic stem cell transplantation: an EBMT study on behalf of the acute leukemia working party (ALWP) and the pediatric diseases working party (PDWP).
    Fabio Andreozzi, Jacques-Emmanuel Galimard, Johan Maertens, Mahmoud Aljurf, Katherine Clesham, Jaime Sanz, Sebastien Maury, Sandrine Loron, Jakob Passweg, Thomas Schroeder, Urpu Salmenniemi, Gwendolyn van Gorkom, Regis Peffault de Latour, Peter A von dem Borne, Franco Locatelli, Robert F Wynn, Jean-Hugues Dalle, Jordi Esteve, Arnon Nagler, Katharina Kleinschmidt, Mohamad Mohty, Krzysztof Kalwak, Fabio Ciceri.
      Acute myeloid leukemia (AML) with translocation (6;9)(p23;q34) is a rare and high-risk disease, frequently co-occurring with FLT3-ITD alteration. We retrospectively analyzed 544 patients with t(6;9) AML undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) and reported to the EBMT registry, between 2000 and 2022. At 2-years, overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), non-relapse mortality (NRM) and GVHD-free/relapse-free survival (GRFS) were 65.7%, 59.1%, 23.0%, 17.9% and 45.6% respectively. The 431 patients transplanted in first complete remission (CR1) had more favorable OS (71.7%), LFS (65.8%) and RI (18.2%). Pediatric and adolescent/young adult (AYA, ≤ 39 years) patients in CR1 had improved outcomes. In patients ≥ 40 years old, OS, LFS, and NRM gradually worsened, whereas significant increase in RI and decrease in GRFS were observed after 53 years. In a matched-pair analysis performed on 76 FLT3-ITD positive and 76 negative CR1 patients, FLT3-ITD was associated with an approximately three-fold higher RI risk, without differences in OS. In conclusion, allo-HSCT in t(6;9) AML provides relatively favorable outcomes especially when performed in CR1. Pediatric and AYA patients derived the greatest benefit from transplant. FLT3-ITD positivity remains a relevant risk factor for relapse, though without impact on OS.
    DOI:  https://doi.org/10.1038/s41409-026-02857-6
  15. Haematologica. 2026 Apr 23.
    Recovering from a therapeutic stall in higher-risk myelodysplastic syndromes: re-examining biology, backbones and study designs.
    Sudhir Tauro, Ayalew Tefferi.
      Therapeutic progress in higher-risk myelodysplastic syndromes (HR-MDS) has stalled. Despite repeated attempts to improve outcomes through incremental refinements to classification systems and hypomethylating agent (HMA)-based backbones, no phase 3 study since AZA-001 has replicated even the modest survival benefit observed with azacitidine. We propose that this stagnation results from a fundamental mismatch between the biological realities of HR-MDS and the assumptions underpinning contemporary drug development. HR-MDS encompasses biologically diverse ecosystems characterised by distinct clonal architectures, evolutionary trajectories and marrow microenvironmental dysfunction, despite overlapping phenotypic and genotypic features. Treating this heterogeneity as a single entity anchored to a hypomethylating agent backbone, risks obscuring therapeutic signals and misinterpreting responses. Here, we examine the potential biological, microenvironmental, and methodological drivers of therapeutic insufficiency in HR-MDS, to advocate for biologically coherent adaptive platform trials using biomarker-enriched patient selection, and propose shifting away from default HMA backbones. Only by redesigning strategy around biology, rather than prioritising ease of recruitment, or historical precedent, can we restore momentum and lift in HR-MDS drug development.
    DOI:  https://doi.org/10.3324/haematol.2026.300560
  16. Stem Cell Reports. 2026 Apr 23. pii: S2213-6711(26)00105-0. [Epub ahead of print] 102894
    TOE1 is a β-catenin interacting protein regulating the proliferation of hematopoietic cells through PAK2 modulation.
    Hyun Park, Okan Sevim, Megan Wagstaff, Aaron Goff, David A Palmer, Bomee Kim, Kate Heesom, Allison Blair, Sarah F Newbury, Ethan L Morgan, Benjamin P Towler, Timothy J Chevassut, Rhys G Morgan.
      Acute myeloid leukemia (AML) is an aggressive hematological malignancy frequently exhibiting deregulated expression/activity/localization of the Wnt signaling mediator β-catenin. To derive more effective β-catenin targeting strategies, we previously interrogated its interaction network in myeloid cells and identified several putative novel interacting partners, including Target of EGR1 (TOE1); a deadenylase with unknown function in hematological tissue. This study aimed to define TOE1 function in hematopoietic cells and uncover its molecular targets. TOE1 interacted with β-catenin in both primary and immortalized AML cells, and impacted Wnt signaling output through the modulation of lymphoid enhancer-binding factor-1 (LEF-1). AML samples exhibited deregulated TOE1 expression versus normal hematopoietic stem/progenitor cells (HSPCs), and TOE1 depletion suppressed the proliferation of myeloid leukemia cell lines, and primary human HSPCs, partly through a p21-activated-kinase 2 (PAK2) mediated mechanism. In summary, these data reveal TOE1 as a novel regulator of hematopoietic cell proliferation via the modulation of important growth-regulating pathways.
    Keywords:  AML; HSPC; LEF-1; PAK2; TOE1; Wnt; β-Catenin
    DOI:  https://doi.org/10.1016/j.stemcr.2026.102894
  17. Cell Death Discov. 2026 Apr 24.
    Roles of RRM2 and RRM2B in pyrimidine stress responses and differentiation of acute myeloid leukemia cells.
    Alojzija Brcic, Hrvoje Lalic, Tomislav Smoljo, Klara Bardač, Vilma Dembitz, Romana Penker, Giovanny Rodriguez Blanco, Antonio Bedalov, Dora Visnjic.
      Differentiation therapy offers a promising approach in acute myeloid leukemia (AML) by overcoming the developmental block that maintains leukemic blasts. Increasing evidence indicates that DNA replication stress can promote differentiation rather than cytotoxicity; however, the metabolic mechanisms linking replication stress to differentiation remain poorly defined. Here, we investigated how perturbations in nucleotide metabolism regulate replication stress-driven differentiation. Using metabolomic and functional analyses in AML cell lines, we show that agents inducing differentiation through replication stress, including 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr), dihydroorotate dehydrogenase (DHODH) inhibition, and low-dose cytarabine, converge on disruption of nucleotide pool balance. Low-dose AICAr induced a pyrimidine-purine imbalance, S phase arrest, and enhanced differentiation, whereas high-dose reduced these effects. Although brequinar and cytarabine altered nucleotide metabolism through distinct mechanisms, differentiation induced by all agents was abolished by supplementation with high levels of ribo- and deoxyribonucleosides, confirming that nucleotide imbalance is a central driver. We further identify ribonucleotide reductase (RNR) as a critical modulator of this process. Replication stress induced context-dependent regulation of RNR subunits, with RRM2 upregulated in p53-mutant U937 cells and the p53-responsive RRM2B isoform predominating in p53-wild-type MOLM-13 cells. Consistent with these differences, RRM2 depletion enhanced differentiation in U937 cells without affecting viability but impaired differentiation and survival in MOLM-13 cells. These findings position nucleotide metabolism as a key regulator of AML differentiation and suggest that combining RNR-targeted and checkpoint-modulating strategies could optimize therapeutic responses.
    DOI:  https://doi.org/10.1038/s41420-026-03105-y
  18. Cell Stem Cell. 2026 Apr 23. pii: S1934-5909(26)00122-0. [Epub ahead of print]
    MMRN1-EGFR drives sialylglycan-Siglec immune evasion in AML leukemia stem cells.
    Meixi Peng, Yongxiu Huang, Mengyun Zhang, Qinrong Yan, Lulu Li, Yaoqi Gui, Jingsong Cheng, Yanni Sun, Yi Mo, Wenqiong Xiang, Yongjie Zhang, Li Wang, Qin Wen, Xi Zhang, Yu Hou.
      Leukemia stem cells (LSCs) drive acute myeloid leukemia (AML) relapse and therapy resistance, predominantly through immune evasion. Here, we identify multimerin 1 (MMRN1) as being highly and specifically expressed in LSCs. Mechanistically, MMRN1 activates the epidermal growth factor receptor (EGFR)/signal transducer and activator of transcription 1 (STAT1) pathway via its epidermal growth factor (EGF)-like domain, suppressing Neu5Ac degradation to drive sialylglycan accumulation, which forms glycoimmune checkpoints functionally akin to programmed death 1 (PD-1)/the cytotoxic T-lymphocyte antigen-4 (CTLA-4). These sialylglycans activate the sialylglycan-Siglec immune checkpoint axis, impairing T/natural killer (NK) cell activity and enabling LSC immune evasion. Additionally, MMRN1 sustains LSC self-renewal via the EGFR/STAT5/CD9 pathway. Genetic ablation of MMRN1 markedly suppresses AML progression and synergizes with anti-PD-L1/CTLA-4 therapy. In a clinical trial (ChiCTR2500097714), erlotinib (an EGFR inhibitor) combined with azacitidine plus the HAG regimen, which consists of homoharringtonine, a low dose of cytarabine, and granulocyte colony-stimulating factor priming, achieves a remission rate of 75% in relapsed/refractory AML, likely via MMRN1/EGFR axis blockade. Our findings establish MMRN1 as a dual-functional target for LSC maintenance and immune evasion and propose that disrupting MMRN1 or EGFR remodels the immunosuppressive tumor microenvironment, offering a promising strategy for AML immunotherapy.
    Keywords:  MMRN1; immune escape; leukemia stem cell; sialylglycans; stemness
    DOI:  https://doi.org/10.1016/j.stem.2026.03.012
  19. Blood Neoplasia. 2026 May;3(2): 100218
    Pharmacological boosting of azacitidine/venetoclax in acute myeloid leukemia.
    Niels Westra, Elena Ropero Cerro, Edwin Schilder, Marjolijn N Lub-de Hooge, Daan J Touw, Jos G W Kosterink, Dana A Chitu, Emanuele Ammatuna, Saskia K Klein, Peter E Westerweel, Marloes Cuijpers, Marjan Cruijsen, Maarten M F Corsten, Canan Alhan, Lidwine Tick, Jan Jacob Schuringa, Gerwin Huls, Carolien M Woolthuis, Thijs H Oude Munnink.
      Azacitidine/venetoclax is the standard treatment for patients with acute myeloid leukemia (AML) unfit for intensive chemotherapy. Cytochrome P450 3A4 (CYP3A4) is the major metabolizing enzyme for venetoclax, and its inhibition can boost venetoclax. In the HOVON 171 phase 2 trial, patients with AML were treated with azacitidine/venetoclax/cobicistat. This 2-stage, open-label, multicenter phase 2 trial included a crossover run-in phase followed by an ongoing extension phase. In cycle 1, patients received standard-dose azacitidine/venetoclax. In cycle 2, cobicistat was added, and venetoclax was reduced to 50 mg. The primary end point was pharmacokinetic equivalence, defined as 90% confidence interval (CI) of geometric mean ratios (GMRs) >0.8 for area under the curve over 24 hours (AUC0-24h) and maximum plasma concentration (Cmax). Polymorphisms in genes encoding for CYP enzymes were determined. In vitro assays were performed to assess cobicistat's impact on the antileukemic effect of azacitidine/venetoclax in AML cell lines. In 13 evaluable patients, cobicistat-boosted venetoclax at 50 mg achieved higher exposure than standard 400-mg dosing. GMRs were 2.0 (90% CI, 1.4-2.8) for AUC0-24h and 1.4 (90% CI, 1.0-2.0) for Cmax. In the intention-to-treat population, 65% achieved complete remission (CR) or CR with incomplete hematologic recovery. Interpatient variability in venetoclax exposure because of CYP3A4 polymorphisms was reduced by cobicistat. No unexpected toxicities were observed. In in vitro, cobicistat enhanced azacitidine/venetoclax antileukemic effects. In conclusion, cobicistat enhances and optimizes venetoclax exposure, enabling an eightfold dose reduction while maintaining efficacy. The potentiated antileukemic activity positions cobicistat as a promising complementary agent in AML therapy. This trial was registered at www.clinicaltrials.gov as NCT06014489.
    DOI:  https://doi.org/10.1016/j.bneo.2026.100218
  20. Cell Rep Med. 2026 Apr 20. pii: S2666-3791(26)00166-7. [Epub ahead of print] 102749
    Debio 1562M CD37-targeting ADC is highly active and well tolerated in preclinical models of AML and MDS.
    Léo Marx, Josée Hue-Perron, Alain Monjardet, Selena Vigano, Christophe Chardonnens, Kaitlin Morse, Esthela Artiga, Marie-Claude Roubaudi-Fraschini, René Wuttke, Riccardo Colombo, Karilyn Larkin, Lisa Ivanschitz.
      The leukocyte antigen CD37 is broadly expressed on acute myeloid leukemia (AML) blasts and associated with poor prognosis. We demonstrate that myelodysplastic syndrome (MDS) cells also express CD37, and both AML and MDS cells have favorable internalization properties of this receptor. Debio 1562M is a next-generation antibody-drug conjugate (ADC) that targets CD37 and is optimized to deliver more toxins to tumor cells than the first-generation ADC Debio 1562, while maintaining a good safety profile. Preclinically, Debio 1562M showed robust anti-leukemic activity in AML and MDS primary samples and in AML xenograft models, irrespective of disease stage or genotype. Debio 1562M was able to target leukemic stem cells in vitro and significantly decrease tumor burden in blood and bone marrow, resulting in survival prolongation compared with standard-of-care treatments. These data demonstrate that CD37 is a relevant target for both indications and that Debio 1562M is a promising therapeutic candidate.
    Keywords:  CD37; Debio 1562M; Multilink linker technology; acute myeloid leukemia; antibody-drug conjugate; cleavable linker; myelodysplastic syndrome; patient-derived xenografts; preclinical assessment
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102749
  21. Blood Cancer Discov. 2026 Apr 21. OF1-OF5
    Outstanding Questions to Understand and Target Splicing Factor-Mutant Blood Cancers.
    Maxim I Maron, Omar Abdel-Wahab.
      Mutations in genes encoding RNA splicing factors are common in patients with myeloid malignancies and chronic lymphocytic leukemia. In this commentary, we discuss key unanswered questions on the causal role of these mutations in blood cancers and precursor conditions as well as efforts to develop therapies targeting these high-frequency neomorphic mutations.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-26-0047
  22. Hemasphere. 2026 Apr;10(4): e70307
    APL-like subset within NPM1-mutated AML: A distinct immunophenotype correlating with early vascular complications.
    Francesco Mannelli, Francesca Crupi, Sara Bencini, Michaela Feuring, Gaia Ciolli, Matteo Piccini, Marco Frigeni, Raffaele Palmieri, Chiara Sartor, Barbara Scappini, Giacomo Gianfaldoni, Benedetta Peruzzi, Roberto Caporale, Antonio Scannella, Laura Fasano, Elisa Quinti, Andrea Pasquini, Jessica Caroprese, Leonardo Signori, Fabiana Pancani, Chiara Maccari, Tiziana Ottone, Daniela Spaeth, Antonio Curti, Maria Teresa Voso, Francesco Annunziato, Konstanze Döhner, Adriano Venditti, Francesco Buccisano, Alessandro Rambaldi, Paola Guglielmelli, Hartmut Döhner, Alessandro M Vannucchi.
      Among NPM1-mutated acute myeloid leukemia (AML) (NPM1 mut), a distinct subtype has been described with an immunophenotypic profile resembling acute promyelocytic leukemia (APL-like). In this retrospective multicenter study including 384 NPM1 mut AML patients, we identified 95 (24.7%) cases exhibiting an APL-like immunophenotype. This subset was characterized by significant abnormalities in coagulopathy markers (D-dimer, D-dimer/fibrinogen ratio, and disseminated intravascular coagulation [DIC] score). The cumulative incidence of vascular events at 30 days was significantly higher in the APL-like group compared to the non-APL-like group (30.5% vs. 10.1%, P < 0.001). Notably, a higher cumulative incidence of early death due to vascular complications (within 30 days) was observed in the APL-like group (6.3% vs. 0.35% in controls; P = 0.00015). In multivariate analysis, the APL-like immunophenotype was the only significant factor associated with vascular-related early death (hazard ratio [HR] = 19, P = 0.0063). There was a significantly higher rate of IDH1/2 mutations in APL-like (68.3%) compared to non-APL-like (18.3%, P < 0.001) cases. We validated these clinical and molecular findings in an independent validation cohort of 302 NPM1 mut patients enrolled in the acute myeloid leukemia study group (AMLSG) 09-09 clinical trial, which included the administration of all-trans retinoic acid (ATRA) to all patients and a randomization for gemtuzumab ozogamicin. In this cohort, the APL-like immunophenotype was associated with events occurring within the first 15 days but did not influence mortality, likely due to protocol-driven patient selection. Our findings have important clinical implications that warrant the development of studies exploring disease-tailored clinical measures to mitigate the risk of early vascular events, as in current APL management.
    DOI:  https://doi.org/10.1002/hem3.70307
  23. Br J Haematol. 2026 Apr 20.
    Recombinant zoster vaccine induces superior immunogenicity compared with live varicella vaccine in allogeneic haematopoietic stem cell transplantation recipients.
    Takaaki Ono, Takashi Okada, Ryo Ikeda, Mitsuru Yamashita, Katsumi Koyauchi, Fumisato Takagi, Miwa Adachi, Tomonari Takemura, Kozue Mitsui, Yasuyuki Nagata.
      
    Keywords:  allogeneic haematopoietic stem cell transplantation; herpes zoster; recombinant zoster vaccine
    DOI:  https://doi.org/10.1111/bjh.70500
  24. Genes Dis. 2026 Jul;13(4): 101794
    Suppression of UCP2 alleviates leukemogenesis by enhancing branched-chain amino acids-induced oxidative stress via activating the PI3K/AKT/mTOR signaling pathway.
    Agida Okohi Innocent, Yajie Shen, Yixuan Gao, Ruixin Sun, Kasimujiang Aximujiang, Zizhen Xu, Jinke Cheng, Jiao Ma.
      Although the cellular role of uncoupling protein 2 (UCP2) in tumorigenesis has been reported in various solid tumor models, its role in leukemogenesis remains elusive. Herein, we demonstrated that UCP2 was highly expressed in AML and significantly associated with poor prognosis and chemoresistance, suggesting that UCP2 can be used as a potential biomarker in acute myeloid leukemia. Mechanistically, in vitro and in vivo silencing of UCP2 significantly impairs acute myeloid leukemia cell growth and survival, accompanied by the disruption of mitochondrial homeostasis. Interestingly, RNA-sequencing analysis and metabolic mass spectrometry revealed that silencing UCP2 resulted in accumulated branched-chain amino acids (BCAAs), which induced oxidative stress through the PI3K/AKT/mTOR signaling pathway. Additionally, the lack of BCAAs restored leukemic cell growth and survival and decreased mitochondrial ROS production induced by inhibiting UCP2. More importantly, supplementation of BCAA enhanced the anti-tumor activity of genipin, a selective inhibitor that targets UCP2, resulting in significantly reduced acute myeloid leukemia blasts, increased mouse survival, and magnified oxidative stress. Taken together, our study elucidates the rationale of targeting the UCP2-BCAA-PI3K/AKT/mTOR signaling axis in leukemogenesis and provides a novel strategy for leveraging the metabolic dependencies of leukemic cells.
    Keywords:  AML branched-chain amino acids; Leukemogenesis; Oxidative stress; PI3K/AKT/mTORsignaling; UCP2
    DOI:  https://doi.org/10.1016/j.gendis.2025.101794
  25. Haematologica. 2026 Apr 23.
    Novel KAT6B::NUTM2B fusion oncogene in congenital acute myeloid leukemia and implications for menin inhibitor therapy.
    Rebecca K Voss, Wenqing Qi, La'Ron Browne, Ruth W Wang'ondu, Mahsa Khanlari, Jing Ma, Xuefei Ma, Josi Lott, Juan M Barajas, Melvin Thomas Iii, Victor B Pastor Loyola, Hui Cao, Larissa V Furtado, Swati Naik, Sakshi Bami, Seth E Karol, Jeffrey E Rubnitz, Jeffery M Klco, Yen-Chun Liu, Lu Wang.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2025.300350
  26. Am J Surg Pathol. 2026 Apr 20.
    The Clinicopathologic and Genomic Features of Mature Versus Blastic Plasmacytoid Dendritic Cell Neoplasms Arising From Chronic Myeloid Neoplasms.
    Sarah J Wu, Christopher B Hergott, Gabriel K Griffin, Andrew A Lane, Marlise R Luskin, Cecilia A Larocca, Nicole R LeBoeuf, Nana P Matsumoto, Shai Shimony, Brianna F Waller, Waihay J Wong, Robert P Hasserjian, Annette S Kim, Elizabeth A Morgan, Sam Sadigh.
      Clonal mature plasmacytoid dendritic cell proliferations (MPDCP) are a recently recognized entity in the WHO fifth edition, but their pathologic spectrum remains poorly characterized. Cases with extensive MPDCP in the bone marrow (BM) are rare and can exhibit overlapping features with blastic plasmacytoid dendritic cell neoplasm (BPDCN). We compared clinicopathologic and genomic features of 11 patients with myeloid neoplasm-associated MPDCP to 5 patients with secondary BPDCN arising from clonally-related myeloid neoplasms. MPDCP exhibited variable degrees of BM involvement (5% to 50%) and architectural patterns, were uniformly positive for CD123, CD4, TCF4, and IRF8, variably positive for TCL1 (7/11), CD5 (7/11), and CD7 (2/11), and negative for SOX4, CD56, and TdT. MPDCP skin involvement was rare (1/11), with no CNS involvement. MPDCP heralded myeloid disease progression in a subset of patients, with increased blasts or progression to AML (4/11). In contrast, secondary BPDCN was uniformly positive for SOX4 and TCL1, with frequent CD56 (4/5) and subset/weak TdT (3/4). All BPDCN patients had characteristic skin lesions, and a subset with CNS involvement (2/5). The underlying myeloid neoplasms associated with MPDCP or BPDCN were enriched in TET2, SRSF2, ASXL1, RUNX1, and RAS pathway mutations. While karyotypic abnormalities were uncommon in MPDCP, all BPDCN showed chromosomal structural abnormalities and copy number variants, including deletions of 3p, 9p, and 12p. Our findings expand the histopathologic, immunophenotypic, and genetic characterization of MPDCP, and highlight pathologic features that distinguish it from BPDCN. Utilization of SOX4 immunohistochemistry, combined with careful clinical and molecular correlation, can aid in resolving these diagnostic challenges.
    Keywords:  MPDCP; blastic plasmacytoid dendritic cell neoplasm; mature plasmacytoid dendritic cell proliferations; progression of myeloid neoplasms; secondary BPDCN
    DOI:  https://doi.org/10.1097/PAS.0000000000002556
  27. Eur J Haematol. 2026 Apr 21.
    Phase I/II Trial of the FLT3 Kinase Inhibitor XY0206 in Patients With Relapsed/Refractory Acute Myeloid Leukemia.
    Lin Song, Xudong Wei, Zhimin Zhai, Anyou Wang, Daozi Jiang, Yang Liang, Fei Li, Zhongxing Jiang, Xuejun Zhang, Qunyi Guo, Hongmei Jing, Yajing Xu, Xiangmin Tong, Jianmin Wang, Jianxiang Wang, Junyuan Qi.
      This Phase I/II clinical trial (NCT04471064) evaluated the preliminary efficacy, safety, and pharmacokinetics of XY0206, a novel oral FMS-like tyrosine kinase 3 (FLT3) inhibitor, in patients with relapsed or refractory acute myeloid leukemia (R/R AML). From September 2020 to December 2022, this open-label, multicenter study enrolled patients aged ≥ 18 years with R/R AML. The trial included dose-escalation and dose-expansion phases, with six cohorts receiving XY0206 at doses ranging from 12.5 to 62.5 mg once daily or 25 mg twice daily. Of the 61 enrolled participants, 37 had FLT3 mutation-positive (FLT3mut+) AML. The overall response rate (ORR) was 34.4% in the entire cohort and 48.6% in FLT3mut+ patients. Among FLT3mut+ patients, the composite complete remission rate (CRc) was 45.9%, including a complete remission (CR) rate of 5.4% and a CR with partial hematologic recovery (CRh) rate of 13.5% and a CR with incomplete hematologic recovery (CRi) rate of 27.0%. In patients with FLT3 internal tandem duplication (FLT3-ITD) mutations, the ORR was 56.7%, with a CRc of 53.3% (CR: 6.7%; CRh: 16.7% ; CRi: 30.0%). The 37.5 mg dose cohort, identified as the target dose, was expanded exclusively for FLT3mut+ patients. XY0206 exhibited a favorable safety profile and demonstrated potent antileukemic activity, particularly in FLT3mut+ R/R AML patients, supporting its further clinical development. Trial Registration: CTR20201214 (CDE); ClinicalTrials.gov ID: NCT04471064.
    Keywords:  FLT3 inhibition; acute myeloid leukemia; relapsed/refractory
    DOI:  https://doi.org/10.1111/ejh.70164
  28. Hematology. 2026 Dec 31. 31(1): 2664314
    XPO1 inhibitor selinexor suppresses homologous recombination by inhibiting E2F7 nuclear export in acute myeloid leukemia.
    Chunli Xu, Dandan Wang, Ruiqi Chen, Xu Feng, Feng Cheng, Yu Chen.
       OBJECTIVES: Aberrant nucleocytoplasmic transport mediated by Exportin 1 (XPO1) contributes to leukemogenesis, yet the molecular basis underlying the limited efficacy of the XPO1 inhibitor Selinexor in acute myeloid leukemia (AML) remains unclear. This study aimed to define the role of XPO1 in AML and elucidate the mechanism by which Selinexor regulates homologous recombination (HR).
    METHODS: Public AML datasets and patient samples were analyzed to assess XPO1 expression and clinical relevance. Functional assays evaluated the effects of XPO1 knockdown on AML cell proliferation, apoptosis, and cell cycle progression. Transcriptomic analysis, immunoprecipitation, subcellular fractionation, DNA damage assays, and direct HR functional assays were used to investigate Selinexor-mediated mechanisms. Drug interaction analyses assessed the combined effect of Selinexor and Mitoxantrone.
    RESULTS: XPO1 was significantly overexpressed in AML, particularly in relapsed cases, and high expression was associated with poor prognosis. XPO1 knockdown suppressed proliferation, induced apoptosis, and caused cell cycle arrest. High XPO1 expression correlated with activation of the HR pathway. Mechanistically, Selinexor disrupted the interaction between XPO1 and the transcriptional repressor E2F7, resulting in nuclear retention of E2F7 and downregulation of BRCA1 and RAD51. E2F7 silencing reversed Selinexor-induced HR suppression and DNA damage. In addition, Selinexor synergized with Mitoxantrone to enhance DNA damage and apoptosis in AML cells.
    DISCUSSION: E2F7-mediated HR inhibition is a key mechanism underlying Selinexor activity in AML.
    CONCLUSION: The XPO1-E2F7-HR axis represents a potential therapeutic vulnerability, supporting the rational combination of Selinexor with DNA-damaging agents to improve AML treatment outcomes.
    Keywords:  AML; BRCA1; E2F7; Mitoxantrone; Selinexor; XPO1; homologous recombination; nuclear retention
    DOI:  https://doi.org/10.1080/16078454.2026.2664314
  29. Blood. 2026 Apr 22. pii: blood.2025033031. [Epub ahead of print]
    Extended HLA Haplotypes and Transplant Survival.
    Effie W Petersdorf, Caroline McKallor, Mari Malkki, Meilun He, Stephen R Spellman, Ted A Gooley, Philip A Stevenson.
      The benefit of extended HLA class I~class III~class II haplotypes in the reduction of mortality after hematopoietic-cell transplantation is unknown and requires information on functional class III variation. We identified a robust class III single-nucleotide-polymorphism (SNP), rs915654, informative for mortality and relapse in 1,436 patients and their haploidentical related donors through multivariable regression analysis of 26 candidate class III SNPs. Three-marker haplotypes as defined by one class I locus, one class II locus and rs915654 were determined in patients separately from donors. Inclusion of rs915654 into relapse and mortality models already containing patient HLA-E~DRB1 and donor HLA-B~DRB1 improved each model (likelihood ratio test P=0.06 and 0.004 respectively for relapse; P=0.10 and 0.01 respectively for mortality). The risks of mortality and relapse increased with decreasing numbers of favorable patient and donor markers. Re-testing in an independent cohort of 1,141 haploidentical transplants yielded similar results. The number of unfavorable markers additionally increased non-relapse mortality. HLA-A~C~B~DRB1~DQB1 haplotypes were defined according to their expected numbers of favorable markers, and the theoretical utility for selecting donors was explored. In summary, extended HLA class I~class III~class II haplotypes influence the success of transplantation and inform the biology of the MHC in health and disease. The selection of haploidentical donors for future patients may be optimized with knowledge of donor HLA haplotypes.
    DOI:  https://doi.org/10.1182/blood.2025033031
  30. Leuk Lymphoma. 2026 Apr 23. 1-11
    MBP1 inhibits AML proliferation through downregulating noncanonical Wnt/Ca2+ signaling pathway.
    Beibei Gao, Wenli Yan, Jingjing Xue, Shanshan Zhang, Furong Wang, Zhijie Kang, Jinhong Ren, Jinsong Yan, Haina Wang.
      Acute myeloid leukemia (AML) remains therapeutically challenging, highlighting an urgent need for novel therapeutic targets. Our prior work showed ENO1 promotes AML, but the role of its short variant MBP1 was unknown. Here, we demonstrated significant downregulation of MBP1 alongside ENO1 upregulation in primary AML patient samples compared to healthy donors, establishing an imbalanced ENO1/MBP1 ratio. Functionally, restoring MBP1 expression in AML cell lines (KG1, OCI-AML3) inhibited cell proliferation, suppressed colony formation, induced cell apoptosis, and triggered G1-phase cell cycle arrest in vitro. Mechanistically, RNA-seq and pathway analysis revealed that MBP1 overexpression suppresses the non-canonical Wnt/Ca2+ signaling pathway by downregulating its key components Wnt11 and NFATc1. Crucially, in vivo studies using NSG mouse xenografts confirmed that MBP1 overexpression significantly attenuated AML progression, reducing tumor burden in spleen and bone marrow. These results demonstrate that MBP1 deficiency promotes AML via Wnt11/NFATc1 activation, revealing a promising therapeutic target.
    Keywords:  AML; AML leukemogenesis; ENO1; MBP1; NFATc1; Wnt11
    DOI:  https://doi.org/10.1080/10428194.2026.2661083
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