bims-tremyl 2026-03-29 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2026–03–29
34 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Molecular-Based Ecosystem to Improve Personalized Medicine in Chronic Myelomonocytic Leukemia.
Outcomes of Patients Treated With Dasatinib 50 mg/d: A Pooled Analysis.
Metabolite-induced DNA damage drives stochastic stem cell loss and clonal hematopoiesis.
Aberrant oxidative metabolism selects for TET2 -deficient hematopoietic stem and progenitor cells.
Myeloproliferative neoplasms with concomitant chronic myeloid leukemia are associated with TKI resistance and poor outcomes.
Survival after intensive therapy or clofarabine in fit older adults with acute myeloid leukemia: E2906 phase 3 trial.
Clonal hematopoiesis in telomere biology disorders.
Impact of allogeneic stem cell transplantation in patients with higher risk myelodysplastic syndromes.
Ropeginterferon alfa-2b for pre-fibrotic myelofibrosis and lower-risk myelofibrosis requiring cytoreduction.
Genetic alterations and measurable residual disease in core binding factor acute myeloid leukemia.
Iron overload damages mitochondria and induces metabolic rewiring of hematopoietic stem cells towards glycolysis.
The interaction between NPMc+ and Orai1 induces abnormal calcium influx to facilitate leukemogenesis.
Bortezomib Restores Venetoclax Sensitivity in Acute Myeloid Leukemia Cell Lines with Intrinsic and Acquired Resistance.
Treatment of therapy-related acute myeloid leukemia and acute myeloid leukemia with myelodysplasia-related changes: a comparative analysis of higher-dose intensive 7+3 induction chemotherapy versus liposomal cytarabine and daunorubicin.
A Perturb-seq map of a differentiation hub reveals synergistic vulnerabilities in KMT2A-rearranged acute myeloid leukemia.
Peripheral blood stem cells versus bone marrow graft for non-T-depleted haploidentical transplantation with post-transplant cyclophosphamide in patients with secondary acute myeloid leukemia in first complete remission: A study from the ALWP/EBMT.
Mesothelin Promotes Acute Myeloid Leukemia Progression through LYN-dependent Signaling.
Autophagy and Lipid Metabolism as a Therapeutic Target for Overcoming Drug Resistance in Acute Myeloid Leukemia.
Chemotherapy-driven expression of WNT ligands in bone marrow stromal cells contributes to chemoresistance in acute lymphoblastic leukaemia.
IGH::FENDRR and specific KRAS mutations define a novel B-ALL molecular subtype with poor chemotherapy response.
Flare of clonal hematopoiesis, TP53 expansion and prior melphalan drive post-CAR-T myeloid disorders in multiple myeloma.
Autophagy inhibition potentiates the antileukemic effect of FLT3 inhibitors and overcomes resistance in FLT3-ITD acute myeloid leukemia.
Single-cell transcriptional consequences of leukaemogenic SETBP1 mutations.
FLT3-ITD scaffolds PKCι-STAT1 to drive noncanonical S727 phosphorylation and CD276-driven CD8+ T-cell exhaustion in AML.
Synergizing hypomethylating agents with off-the-shelf CD70-targeted chimeric antigen receptor-engineered natural killer T cells for the treatment of acute myeloid leukemia.
Results from the prospective phase 2 multicentre UK PBSC haplo trial using PTCy pre- or post-stem cells.
Tyrosine kinase inhibitors, chronic myeloid leukemia, and pregnancy: pharmacotherapeutic challenges and recommendations.
Dynamic epigenetic regulation of BCLAF1 splicing in acute myeloid leukemia.
A synergistic interaction between PRMT5 and LSD1 inhibitors in AML.
RNF25 confers mRNA damage tolerance by curbing activation of the integrated stress response.
Genetic influences on haematopoiesis.
LSD1 inhibition ameliorates congenital dyserythropoietic anemia type II.
A bispecific anti-fluorescein x anti-CD3 T-cell engager in combination with fluoresceinated adaptors enables lysis of AML cells.
Leveraging paired germline and somatic analysis to improve the classification of DDX41 variants.

J Clin Oncol. 2026 Mar 27. JCO2502116

Molecular-Based Ecosystem to Improve Personalized Medicine in Chronic Myelomonocytic Leukemia.

iCPSS Alliance

PURPOSE: Chronic myelomonocytic leukemia (CMML) is a rare myeloid neoplasm characterized by clinical heterogeneity and is associated with poor outcomes. To date, limited molecular information has been incorporated into disease classification and risk stratification. We aimed to integrate genomic features into the clinical decision-making process for CMML.
PATIENTS AND METHODS: We analyzed a retrospective cohort of 3013 patients with CMML (training set) and a prospective population of 516 patients (validation set). Using an innovative framework for multimodal data analysis, we developed molecular-based disease taxonomy and prognostication.
RESULTS: Unsupervised clustering identified nine entities with distinct genomic features and outcomes (P < .001), including splicing machinery, transcription factors, signal transduction and tyrosine kinase pathways aberrations, and high-risk molecular signatures. Notably, 15% of patients showed molecular/clinical overlap with other myeloid neoplasms. We integrated molecular and clinical information to build the international CMML Prognostic Scoring System (iCPSS), incorporating mutations in nine genes together with hematologic parameters and cytogenetic abnormalities. The iCPSS identified five groups with distinct probability of overall and leukemia-free survival in both training and validation cohorts (P < .001), outperforming existing prognostic models. Importantly, 55% of patients were reassigned to higher or lower risk groups by the iCPSS. Decision analysis demonstrated that iCPSS could refine the optimal timing of allogeneic transplantation at the individual level; compared with conventional prognostic tools, iCPSS-based decision modeling changed transplantation strategy in 31% of cases, resulting in a significant gain-in-life expectancy for eligible patient population (P < .001). A federated learning platform was implemented to enable continuous, privacy-preserving model update across multiple centers.
CONCLUSION: Molecular information improves CMML classification and prognostication, supports more effective clinical decision making, and potentially refines the design of clinical trials.

DOI: https://doi.org/10.1200/JCO-25-02116
Clin Lymphoma Myeloma Leuk. 2026 Mar 03. pii: S2152-2650(26)00063-7. [Epub ahead of print]

Outcomes of Patients Treated With Dasatinib 50 mg/d: A Pooled Analysis.

Fadi G Haddad, Elias Jabbour, Koji Sasaki, Samuel Black, Jonathan Michael Savoy, Yesid Alvarado, Gautam Borthakur, Naveen Pemmaraju, Musa Yilmaz, Sara Delasalla, Ghayas C Issa, Hagop Kantarjian.

   BACKGROUND: Dasatinib is approved at 100 mg/d for newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). We report outcomes with frontline dasatinib 50 mg/d in a large cohort of patients with CML-CP.
METHODS: In a phase II clinical trial, patients with newly diagnosed CML-CP received dasatinib 50 mg/d alone (n = 83) or in combination with venetoclax (n = 66). We evaluated the molecular response rates, incidence of adverse events, event-free survival (EFS), and overall survival (OS).
RESULTS: One hundred forty-nine patients were included; the median age at diagnosis was 46.7 years (range, 19.9-84.3); Sokal risk was high-risk in 7 patients (4.7%). By 60 months of dasatinib therapy, the cumulative rates of major molecular response, MR4, and MR4.5 were 95%, 87%, and 86%, respectively. With a median follow-up of 73 months, the 5-year EFS and OS rates were 96% and 98%, respectively. Adverse events were observed in 72 patients (48%), including pleural effusion in 19 (12.7%), of which 3 (2%) of Grade 3. Eighteen patients (12%) discontinued dasatinib due to adverse events.
CONCLUSION: The long-term follow-up confirms the safety and efficacy of dasatinib 50 mg/d in patients with newly diagnosed CML-CP.

Keywords:  Chronic myeloid leukemia; Pleural effusion; Response; Toxicity; Tyrosine kinase inhibitor

DOI:  https://doi.org/10.1016/j.clml.2026.02.013
Cell Stem Cell. 2026 Mar 23. pii: S1934-5909(26)00081-0. [Epub ahead of print]

Metabolite-induced DNA damage drives stochastic stem cell loss and clonal hematopoiesis.

Ashley N Kamimae-Lanning, Jill M Brown, Matthias Günther, Franziska Esau, Holly Russell, Lise Larcher, Frédéric Langevin, Tomoya Isobe, Nicola K Wilson, Felix A Dingler, Rebecca L Cordell, Meng Wang, Christopher L Millington, Nina Claudino, Ewa Gogola, Matthew Nicholls, Verena Körber, Berthold Göttgens, Marella F T R de Bruijn, Juan I Garaycoechea, Jean Soulier, Thomas Höfer, Ketan J Patel.

  DNA damage and mutations in hematopoietic stem cells (HSCs) enable clonal hematopoiesis (CH). Such damage occurs across a lifetime, but its origins remain unknown. Here, we demonstrate that endogenous formaldehyde causes HSC attrition and subsequently CH. We generated conditional mouse models lacking formaldehyde detoxification and Fanconi anemia (FA) DNA repair in blood. Formaldehyde protection was crucial for embryonic HSC emergence and throughout life. Despite severe deficiencies in HSCs, these mice produced blood for many months. To determine what enables this, we employed an unbiased method for detecting clones, which exploits somatic variant data. This revealed initial polyclonal hematopoiesis that diminishes to monoclonal hematopoiesis, devoid of known genetic selection. Furthermore, in FA children, we find the same transition to monoclonal hematopoiesis. Therefore, DNA damage-induced attrition down to the last functional cell can be a driving force for CH, representing an alternative route to CH other than purely by fitness-enhancing selection.

Keywords:  Fanconi anemia; HSC attrition; bone marrow failure; clonal hematopoiesis; endogenous DNA damage; formaldehyde; neutral drift; somatic evolution; stem cell aging

DOI:  https://doi.org/10.1016/j.stem.2026.02.011
bioRxiv. 2026 Mar 02. pii: 2026.02.28.707294. [Epub ahead of print]

Aberrant oxidative metabolism selects for TET2 -deficient hematopoietic stem and progenitor cells.

Katia E Niño, Vera Adema, Alyx E Gray, Courtney M Cowan, Wolfgang E Schleicher, Mohsen Hosseini, Sierra N Bennett, Sweta B Patel, Steven Moreira, Etienne Danis, Feiyang Ma, Hsin-Ying Lin, Tracy N Young, Colin A Anderson, Devyani Sharma, Angelica Varesi, Marie-Dominique Filippi, Keisuke Ito, Meelad M Dawlaty, Gang Huang, Julie A Reisz, Stephanie Z Xie, Steven M Chan, Lin Tan, Guillermo Garcia-Manero, Kelly Chien, Irene Gañan Gomez, Angelo D'Alessandro, Simona Colla, Eric M Pietras.

The mechanism(s) driving selective expansion of mutant hematopoietic stem and progenitor cells (HSPC) in clonal hematopoiesis (CH) are incompletely understood. Here, we address the role of metabolism in selection for HSPC with loss of function mutations in TET2 . Loss of Tet2 in murine HSPC triggers overexpression of glycolysis and oxidative phosphorylation genes and increased oxidative metabolism via an enlarged mitochondrial network. However, Tet2 -deficient HSPC maintain a normal redox state. Strikingly, compound loss of the rate-limiting pentose phosphate pathway (PPP) enzyme glucose-6-phosphate dehydrogenase (G6PD) triggers increased reactive oxygen species and impairs the fitness of Tet2 -deficient HSPC. We find that aberrant oxidative metabolism is also a feature of HSPC in human CH and clonal cytopenia of unknown significance (CCUS). Overall, our data point to aberrant metabolism as a critical and conserved driver of selection in TET2 -deficient CH and identify the PPP as a crucial compensatory pathway needed to maintain their selective advantage.
Statement of Significance: This study identifies oxidative metabolism as a critical driver of selection for TET2 -deficient HSPC in clonal hematopoiesis (CH). It also demonstrates that cellular redox state is a vulnerability that impairs their fitness. These insights establish targetable metabolic pathway(s) that could be exploited in the setting of TET2 mutant CH.

DOI: https://doi.org/10.64898/2026.02.28.707294
Leukemia. 2026 Mar 27.

Myeloproliferative neoplasms with concomitant chronic myeloid leukemia are associated with TKI resistance and poor outcomes.

Laura Li Gagnon, Andrea Duminuco, Fabio Stagno, Marta Sobas, Mikhail Fominykh, Andres Virchis, Franck-Emmanuel Nicolini, Julie Hildt, Helen Bentley, Anna L Godfrey, Lee-Yung Shih, Ashlyn Chee, Adam Mead, Krzysztof Lewandowski, Patryk Sobieralski, Guy Hannah, Yasmin Reyal, Thomas Cummin, Jaroslaw Piszcz, Kawai Yip, Rebecca Frewin, Srinivasan Narayanan, Deborah Rahman, Alero Ajayi, Paul Cervi, Jennifer Byrne, Tom Taylor, Weronika Lebowa, Jiri Pavlu, Siamak Arami, Mansour Ceesay, Dominik Chraniuk, Robert Delage, Annalisa Condorelli, Clémence Santana, Deepti H Radia, Hugues de Lavallade, Dragana Milojkovic, Claire Harrison, Patrick Harrington.

Chronic myeloid leukemia (CML) and Philadelphia (Ph)-negative myeloproliferative neoplasms (MPN) are generally distinct clonal disorders, with the co-occurrence of BCR::ABL1 rearrangement with concomitant Ph-negative MPN rarely reported. Here we describe the largest known international cohort of Ph-negative MPN and coexisting CML providing important insights into this rare clinical scenario. We performed an international, multicenter, retrospective analysis of patients with concomitant BCR::ABL1 rearrangement and Ph-negative MPN, identifying 61 cases from 30 centers in 7 countries, over a 29-year period (1996-2025). Thirty-one patients (50.8%) had Ph-negative MPN preceding CML, 18 patients (29.5%) had CML preceding Ph-negative MPN, and 12 patients (19.7%) had Ph-negative MPN and CML diagnosed simultaneously. We observed increased TKI resistance and myelofibrotic transformation, especially in patients initially diagnosed with Ph-negative MPN. In this group, 35.4% (n = 11) progressed to MF, 2 patients to blast-phase MPN, and 69.2% (n = 18) failed to achieve a complete cytogenetic response. The rare e1a2 BCR::ABL1 transcript was notably prevalent which is associated with TKI resistance and a more aggressive disease course in CML. We described superior survival in those with Ph-negative MPN preceding CML, with median OS not reached, compared with 277 months for CML preceding Ph-negative MPN and 100 months for those diagnosed simultaneously (p = 0.05).

DOI: https://doi.org/10.1038/s41375-026-02928-z
Blood Neoplasia. 2026 May;3(2): 100194

Survival after intensive therapy or clofarabine in fit older adults with acute myeloid leukemia: E2906 phase 3 trial.

James M Foran, Zhuoxin Sun, Selina M Luger, David F Claxton, Hillard M Lazarus, Daniel A Arber, Jacob M Rowe, Elisabeth Paietta, Janis Racevskis, Fran Garrett-Bakelman, Yanming Zhang, Jessica K Altman, Aref Al-Kali, Hong Zheng, Keith W Pratz, E Randolph Broun, Bayard L Powell, Kristen Marie O'Dwyer, John E Godwin, Yishai Ofran, Mark R Litzow, Martin S Tallman.

Clofarabine is a second-generation purine nucleoside analog with encouraging reported 30-day induction mortality (IM) and complete remission (CR) or CRi (incomplete platelet recovery) rates, and represents a lower-intensity therapy for older adults with acute myeloid leukemia (AML). We evaluated long-term outcomes in a prospective phase 3 study using a noninferiority design. Patients aged ≥60 years with newly diagnosed AML and normal renal and cardiac function were randomized to standard intensive daunorubicin and cytarabine or single-agent clofarabine. The primary objective was overall survival (OS) using a weighted analysis. We incorporated prospective central testing for measurable residual disease (MRD; ≥0.1%) at remission using multiparameter flow cytometry. Among 727 patients (standard, n = 363; clofarabine, n = 364), there was no difference in CR/CRi (50%) or IM (8.5%) rates. The median follow-up was 58.6 months. In the primary analysis, OS was inferior with clofarabine (median, 10.4 vs 12.4 months [standard]; P = .04), although not in patients aged ≥70 years, with secondary AML, or unfavorable cytogenetics. Allogeneic transplantation was strongly associated with OS on multivariate analysis (HR, 0.53; P < .0001). MRD-negative remission was achieved in 41% of patients and strongly associated with 5-year OS irrespective of treatment (MRD-positive, 48.8% vs 12.2%; P = .003). In contrast, MRD-positive patients assigned to clofarabine (vs high-dose cytarabine) consolidation had significantly inferior OS. Clofarabine is inferior to standard intensive therapy despite similar remission rates. Achieving MRD-negative remission is associated with high, sustained rates of OS regardless of therapy. Increasing MRD negativity and improving outcomes among MRD-positive patients remain pressing, ongoing challenges. This trial was registered at www.clinicaltrials.gov as NCT02085408.

DOI: https://doi.org/10.1016/j.bneo.2026.100194
Semin Hematol. 2026 Feb 28. pii: S0037-1963(26)00013-2. [Epub ahead of print]

Clonal hematopoiesis in telomere biology disorders.

Christopher M Sande, Daria V Babushok.

  Telomere biology disorders (TBDs) are a group of genetic conditions of varying severity caused by defects in telomere maintenance. Patients with TBDs can experience dysfunction in nearly all organ systems, including the bone marrow, with increased risk for bone marrow failure and myeloid neoplasms. Over the past decade, several groups have identified higher rates and earlier onset of clonal hematopoiesis (CH) in TBDs patients, with a distinct profile of somatic variants compared to the general population. While TBDs patients sometimes develop variants seen in age-related CH, these are proportionally much less prevalent in TBDs. Instead, TBDs patients develop recurrent gene variants that overcome cell growth constraints caused by telomere shortening or dysfunction. These variants include those that enhance telomere maintenance through reversion of the underlying TBD-causing germline variant or through compensatory mutations in other telomere maintenance machinery, mutations in spliceosome genes, and mutations that disrupt components of the DNA damage response. Early links between specific types of variants and subsequent progression to myeloid malignancies have been reported. In this manuscript, we critically review the existing literature, highlighting open questions in the field, and discuss clinical tools for detecting and monitoring CH in patients with TBDs.

Keywords:  Clonal hematopoiesis; DNA damage response; Dyskeratosis congenita; Somatic mutations; Somatic reversion; Telomere biology disorders

DOI:  https://doi.org/10.1053/j.seminhematol.2026.02.004
Blood Cancer J. 2026 Mar 27.

Impact of allogeneic stem cell transplantation in patients with higher risk myelodysplastic syndromes.

Alexandre Bazinet, Alex Bataller, Kelly Chien, Koji Sasaki, Guillermo Montalban-Bravo, Danielle Hammond, Ian Bouligny, Mahesh Swaminathan, Wei Ying Jen, Eitan Kugler, Rashmi Kanagal-Shamanna, Tapan Kadia, Gautam Borthakur, Courtney DiNardo, Nicholas Short, Naveen Pemmaraju, Elias Jabbour, Naval Daver, Farhad Ravandi, Samuel Urrutia, Georgina Gener-Ricos, Julie Braish, Robert Briski, Juan Jose Rodriguez-Sevilla, Ziyi Li, Richard E Champlin, Elizabeth J Shpall, Amin Alousi, Betul Oran, Chitra Hosing, Jeremy L Ramdial, Amanda Olson, Sherry Pierce, Julianne Chen, Hagop Kantarjian, Guillermo Garcia-Manero, Uday Popat.

Allogeneic stem cell transplantation (SCT) is a curative treatment in myelodysplastic syndromes (MDS). We performed a retrospective single center study of all patients with newly diagnosed higher risk (HR) MDS (IPSS-R > 3.5 points) between 2000 and 2023. We identified 2045 patients with HR-MDS, of which 427 (21%) underwent SCT. The median post-SCT overall survival (OS) was 23.9 months, progression-free survival (PFS) was 14.4 months, 5-year cumulative incidence (CI) of relapse was 37%, and 5-year CI of treatment-related mortality (TRM) was 25%. There were no significant differences in OS, PFS, CI of relapse, or CI of TRM between age categories. Survival improved over the observation period (median 11.8 months in 2000-2010, 28.2 months in 2011-2016, and 40.2 months in 2017-2023; p = 0.01). By multivariate analysis, TP53 status was the most important predictor of post-SCT OS. Patients with TP53-wild type MDS had an OS of 69% at 5 years (HR for death 0.32 with SCT, p < 0.001). Patients with TP53 mutations had poor outcomes, with OS of 9.1 months in monoallelic (HR for death 0.88 with SCT, p = 0.69) and 6.8 months in biallelic (HR for death 0.76 with SCT, p = 0.14). SCT can lead to excellent long-term survival in TP53-wild type HR MDS.

DOI: https://doi.org/10.1038/s41408-026-01479-x
Blood Adv. 2026 Mar 24. pii: bloodadvances.2026019612. [Epub ahead of print]

Ropeginterferon alfa-2b for pre-fibrotic myelofibrosis and lower-risk myelofibrosis requiring cytoreduction.

Harinder Gill, Lester Au, Rita Lok Hay Yim, Paul Lee, Vivian Wing Kan Li, Lynn Chin, Qi Zhang, Po-Yan Chan, Carmen Yu Yan Lee, Tony K Y Wu, Garret M K Leung, Yok-Lam L Kwong.

There is currently no consensus on the optimal treatment for early myelofibrosis (MF). Ropeginterferon alfa-2b (ropeg) is a next-generation monopegylated interferon alfa-2b developed specifically to treat myeloproliferative neoplasms. We conducted a phase 2 study in patients with pre-fibrotic primary MF (pre-PMF), and dynamic international prognostic scoring system (DIPSS) low/intermediate-1 risk fibrotic PMF or secondary myelofibrosis (SMF), who required cytoreduction. Ongoing treatment with hydroxyurea was substituted with ropeg (week 0: 250 mcg; week 2: 350 mcg; week 4 onwards: 500 mcg every 2 weeks). The primary endpoints were safety and clinicohematological complete response (CHCR). Seventy-one patients (40 men and 31 women) with a median age of 60 (range: 31-86) years were enrolled, followed up for a median of 119 (range:10-131) weeks. At weeks 24, 48 and 104, CHCR was achieved in 63.8% (pre-PMF: 74%; fibrotic PMF: 20%; fibrotic SMF: 42.9%), 63.5% (pre-PMF: 69.6%; fibrotic PMF: 25%; SMF: 53.9%) and 70% (pre-PMF: 78.4%; fibrotic PMF: 33.3%; SMF 50%) of patients. Thrombo-hemorrhagic events were not observed after stopping hydroxyurea. At weeks 24, 48 and 104, reduction in JAK2V617F variant allele frequency (VAF) was observed in 53.1%, 70% and 67.6% of patients, and, reduction in CALR mutant VAF was observed in 52.6%, 42.9% and 40% of patients, respectively. In 50 evaluable cases at week 104, 13 patients (26%) had reduced bone marrow reticulin fibrosis. There were 3 treatment discontinuations (4.2%) due to adverse events. In conclusion, ropeg was safe and induced CHCR associated with significant molecular responses in patients with early MF. ClinicalTrials.gov Identifier: NCT04988815.

DOI: https://doi.org/10.1182/bloodadvances.2026019612
Leukemia. 2026 Mar 26.

Genetic alterations and measurable residual disease in core binding factor acute myeloid leukemia.

Loïc Vasseur, Matthieu Duchmann, Nicolas Duployez, Emmanuel Raffoux, Céline Berthon, Maël Heiblig, Alexis Genthon, Thorsten Braun, Mathieu Leclerc, Delphine Lebon, Sylvain Chantepie, Jean-Baptiste Micol, Juliette Lambert, Christian Récher, Marie-Lorraine Chrétien, Alexandre Iat, Julien Vaidie, Jean-Valère Malfuson, Madalina Uzunov, Arnaud Pigneux, Pierre Peterlin, Sihem Tarfi, Pierre Hirsch, Dominique Penther, Eric Jourdan, Karine Celli-Lebras, Claude Preudhomme, Hervé Dombret, Jérôme Lambert, Nicolas Boissel, Raphaël Itzykson.

Measurable residual disease (MRD) is a major prognostic factor in Core Binding Factor (CBF) AML. KIT or FLT3 mutations also have prognostic relevance, but little is known about their prognostic value when accounting for MRD. We analyzed the prognostic value of genetic alterations adjusting for early MRD response in adult CBF-AML patients. We grouped data from the retrospective multicenter study RetroCBF (NCT05070208, training set) and the prospective CBF-2006 trial (NCT00428558, validation set). Centralized high-throughput sequencing was performed with 36 genes. 656 CBF-AML patients in first CR were included between 2007 and 2020 (RetroCBF n = 461; CBF-2006 n = 195). In a LASSO-penalized model including MRD and genetic alterations performed in the RetroCBF training cohort, KIT-TKD in RUNX1::RUNX1T1 and FLT3-ITD in CBFB::MYH11 were associated with a higher risk of relapse. Including these genetic alterations with MRD in the training cohort, 3-year cumulative incidence of relapse was 22% (95%CI:13-33%) in low-risk patients (MRD low AND no KIT-TKD [RUNX1::RUNX1T1] or FLT3-ITD [CBFB::MYH11]) versus 53% (95%CI 46%-60%) in high-risk patients (csHR=3.21 [95%CI:1.83-5.62], p < 0.0001). These results were confirmed in the CBF-2006 validation cohort. KIT-TKD mutations in RUNX1::RUNX1T1 and FLT3-ITD in CBFB::MYH11 worsen prognosis independently of MRD and must be included in risk stratification of CBF AMLs.

DOI: https://doi.org/10.1038/s41375-026-02900-x
Blood. 2026 Mar 24. pii: blood.2025031552. [Epub ahead of print]

Iron overload damages mitochondria and induces metabolic rewiring of hematopoietic stem cells towards glycolysis.

Silvia Sighinolfi, Laura Cassina, Maria Rosa Lidonnici, Stefano Beretta, Davide Stefanoni, Mariangela Storto, Christina Mayerhofer, Trine A Kristiansen, David T Scadden, Ivan Merelli, Alessandra Boletta, Annamaria Aprile, Giuliana Ferrari.

Iron is an essential element for most cellular processes and recent evidence highlighted its role in regulating the function of hematopoietic stem cells (HSCs). Abnormal iron levels impact HSC quiescence and self-renewal, however, the mechanism by which iron overload (IO) influences HSC function is still unknown. Here, we show that intracellular IO impairs mitochondrial fitness and bioenergetics, inducing metabolic rewiring. In thalassemic mice, as a model of chronic IO, HSCs accumulate mitochondria with elevated reactive oxygen species (mtROS), low membrane potential and reduced oxidative phosphorylation (OXPHOS). Mitochondrial defects are confirmed in other two models of IO, sickle cell disease and iron-loaded wild-type mice, and in vivo iron reduction rescues HSC mitochondria. IO HSCs are highly proliferating and in presence of damaged mitochondria rely on glycolysis for energy production. Notably, restoration of mitochondrial function by targeting in vivo mtROS improved the quiescence and self-renewal of IO HSCs. Our results unravel the critical interplay between iron, ROS and mitochondrial activity in HSCs, revealing that IO shapes HSC metabolic programs.

DOI: https://doi.org/10.1182/blood.2025031552
FEBS J. 2026 Mar 24.

The interaction between NPMc+ and Orai1 induces abnormal calcium influx to facilitate leukemogenesis.

Wenhao Zhang, Chuangxuan Liang, Lulu Zhang, Xinglin Liu, Zhenyu Zhang, Huarong Guo, Jie Jia, Xin Chen, Hongxin Shang, Xuena Zheng, Jun Qin, Shan Li, Danwen Liu, Fuyun Wu.

  Nucleophosmin 1 (NPM1) is a ubiquitously expressed phosphoprotein, mainly located in the nucleolus. It is overexpressed in solid tumors and considered a key target in cancer therapy. NPM1 mutations are the most common genetic abnormalities in acute myeloid leukemia (AML), where they are found in about 30% of patients. In AML, NPM1 mutations result in the cytoplasmic localization of the mutant protein NPMc+. Although NPM1 mutations are known to drive AML, the underlying mechanisms are not fully understood. In this study, we found that primary leukemia cells from NPM1-mutated AML patients exhibited elevated intracellular calcium levels compared with cells from NPM1 wild-type AML patients. Our investigation revealed that NPMc+ interacts with the calcium channel Orai1, disrupting calcium homeostasis in AML cells. Notably, we identified that the N-terminal region of NPM1 contains a calcium-binding domain that directly interacts with Orai1, facilitating calcium influx. Targeting NPMc+, Orai1, or the NPMc+/Orai1 complex using small-molecule inhibitors significantly reduced calcium influx, inhibited calcium-related signaling pathways, and suppressed the proliferation of NPM1-mutated AML cells. These findings uncover a novel mechanism in which NPMc+ interacts with Orai1, disrupting calcium homeostasis and promoting AML progression. This presents a promising therapeutic strategy targeting the NPMc+/Orai1-mediated calcium imbalance in NPM1-mutated AML.

Keywords:  NPM1; Orai1; acute myeloid leukemia; calcium influx; calcium signaling

DOI:  https://doi.org/10.1111/febs.70508
Mol Cancer Ther. 2026 Mar 26.

Bortezomib Restores Venetoclax Sensitivity in Acute Myeloid Leukemia Cell Lines with Intrinsic and Acquired Resistance.

Chengxi Li, Yu-Hsuan Chang, Minori Maki, Ikuko Omori, Naru Sato, Susumu Goyama, Toshio Kitamura, Yutaka Enomoto.

Venetoclax, a selective BCL-2 inhibitor, effectively induces apoptosis in a wide range of malignancies. Venetoclax-based regimens, combined venetoclax with either hypomethylating agents or low-dose cytarabine, have markedly improved treatment outcomes in elderly patients with acute myeloid leukemia (AML). However, approximately one-third of patients exhibit intrinsic resistance to these regimens, and the majority of initial responders eventually develop acquired resistance. Therefore, intrinsic and acquired resistance to venetoclax-based regimens remains a major barrier to achieving durable clinical responses in AML patients. In this study, we aimed to identify effective treatment strategies to overcome venetoclax resistance. Among drugs tested in this study, we found that bortezomib, a proteasome inhibitor, showed potent synergy with venetoclax in inducing apoptosis in a wide range of AML cell lines, irrespective of RAS or TP53 mutation status. Mechanistically, bortezomib upregulates pro-apoptotic proteins such as NOXA, BIM, and PUMA, which neutralize MCL1 and promote apoptosis. Notably, NOXA upregulation plays a critical role in the efficacy of the combination of venetoclax and bortezomib. Moreover, bortezomib resensitized AML cell lines with acquired resistance to venetoclax, further supporting its role in overcoming therapeutic resistance. Importantly, the combination of bortezomib and venetoclax significantly prolongs the survival of mice inoculated with venetoclax-resistant AML cell line harboring BAX mutations, which are commonly observed in relapsed AML following venetoclax-based regimens and confer resistance to venetoclax by inhibiting BAX-dependent apoptotic pathway. Collectively, this study provides a rationale for venetoclax-bortezomib combination as a potential strategy to overcome venetoclax resistance in certain AML subsets.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-0986
Haematologica. 2026 Mar 26.

Treatment of therapy-related acute myeloid leukemia and acute myeloid leukemia with myelodysplasia-related changes: a comparative analysis of higher-dose intensive 7+3 induction chemotherapy versus liposomal cytarabine and daunorubicin.

Dimitrios Kotsos, Patrycja Gradowska, Sjoerd J F Hermans, Thomas Pabst, Johan Maertens, Markus Manz, Dimitri A Breems, Bjorn T Gertsen, Soren Lehmann, Bart J Biemond, Berna H Beverloo, Peter J M Valk, Jeroen J W M Janssen, Gert Ossenkoppele, Bob Löwenberg, Gerwin Huls, Marc H G P Raaijmakers, Jurjen Versluis.

Therapy-related acute myeloid leukemia (t-AML) and AML with myelodysplasia-related changes (AML-MRC) are associated with poor outcomes. The liposomal formulation of cytarabine and daunorubicin (CPX-351) improved complete remission (CR) and CR with incomplete hematologic recovery (CRi) rates and overall survival (OS) compared with 'standard' induction (7+3) chemotherapy in a phase-III trial for patients aged 60-75 years. However, 7+3 dosing varies among trials and in clinical practice and it remains unknown whether CPX-351 is superior to 7+3 double-induction regimens including intermediate-dose cytarabine, as the one employed in the HOVON-SAKK-Nordic clinical trials. To address this question, we conducted a post-hoc analysis on t-AML/AML-MRC patients aged ≥60 years enrolled in three HOVON-SAKK-Nordic trials and defined a subset of patients that met the eligibility criteria of the CPX-351 trial and compared their outcomes with those of the CPX-351 arm using reconstructed survival data. CR/CRi rates were higher in the higher-intensity 7+3 cohort (67.8%) compared with CPX-351 (47.7%) with similar median OS between the two cohorts (10.1 months versus 8.9 months respectively, HR = 0.99; 95% CI 0.78-1.26, p=0.95). Thirty-day mortality (4.4% for higher-intensity 7+3 versus 5.9% for CPX-351) and adverse events, including febrile neutropenia (61% for higher-intensity 7+3 versus 68% for CPX-351), were comparable. The data suggest that obligatory double-induction may achieve outcomes similar to CPX-351 in these patients and provide a strong rationale for ongoing clinical trials comparing these regimens.

DOI: https://doi.org/10.3324/haematol.2025.300065
Leukemia. 2026 Mar 25.

A Perturb-seq map of a differentiation hub reveals synergistic vulnerabilities in KMT2A-rearranged acute myeloid leukemia.

Sajesan Aryal, Brittany M Curtiss, Xinyue Zhou, Rui Lu, Changde Cheng.

KMT2A-rearranged acute myeloid leukemia is driven by epigenetic dependencies yet remains clinically resistant to therapies targeting individual regulators, indicating that resistance reflects compensatory regulation across an epigenetic network. A systematic understanding of this compensatory network has been lacking. To address this gap, we utilized Perturb-seq screening to systematically map the functional architecture of this network. We uncovered a compensatory epigenetic circuit, where a synergistic hub including KAT6A, Menin, and DOT1L converges to silence a core differentiation program (the 'Myeloid Program'), thereby maintaining leukemic identity. The activity of this program strongly correlated with favorable survival in large patient cohorts. While individual perturbations of hub components only partially derepress this program, their simultaneous pharmacological inhibition collapses the circuit's buffering capacity, leading to robust reactivation of the Myeloid Program and potent synergistic anti-leukemic activity. Our model also shows that disruption of antagonistic regulators of the Myeloid Program, such as the PRC1.1 component PCGF1, confers strong resistance to DOT1L inhibition. Finally, the Myeloid Program is a predictive biomarker, where high baseline activity defined a vulnerable state that could be selectively targeted by MEK, AKT, and mTOR inhibitors. Together, these findings establish a framework for identifying circuit-level epigenetic compensation and for rationally designing precision combination therapies that restore differentiation or target state-dependent vulnerabilities in acute myeloid leukemia.

DOI: https://doi.org/10.1038/s41375-026-02917-2
Bone Marrow Transplant. 2026 Mar 25.

Peripheral blood stem cells versus bone marrow graft for non-T-depleted haploidentical transplantation with post-transplant cyclophosphamide in patients with secondary acute myeloid leukemia in first complete remission: A study from the ALWP/EBMT.

Arnon Nagler, Ryszard Swoboda, Allain-Thibeault Ferhat, Didier Blaise, Mariya Koc, Anna Maria Raiola, Alessandro Busca, Jiri Pavlu, Stefania Bramanti, Maija Itälä-Remes, Mercedes Colorado, Jan Vydra, Alexander Kulagin, Ali Bazarbachi, Jaime Sanz, Mohamad Mohty, Fabio Ciceri.

Haploidentical stem cell transplantation (haplo-HSCT) with post-transplant cyclophosphamide (PTCy) is a therapeutic option for secondary acute myeloid leukemia (sAML). The study aimed to compare peripheral blood stem cells (PBSC) vs. bone marrow (BM) as a graft source for haplo-HSCT with PTCy in patients with sAML in first complete remission. A total of 554 patients were included, BM = 136, PBSC = 418. Median follow-up was 3 years. The median year of transplant was 2018 (range, 2010-2021). The antecedent hematological disease was myelodysplastic syndrome /myeloproliferative neoplasms in most patients. Patients in the BM group were younger, median age 59.2 vs. 61.7 years (p = 0.008), and received myeloablative conditioning more frequently (66.4% vs. 47.4%, p < 0.001). Time from diagnosis to haplo-HSCT was 5.3 vs. 4.8 months, respectively (p = 0.019). Performance status, cytogenetic risk, gender, cytomegalovirus serostatus, and donor age did not differ. There were no differences between the groups with respect to main transplantation outcomes. In conclusion, outcomes of haplo-HSCT with PTCy in sAML with either PBSC or BM grafts are similar, with no differences in major transplantation outcomes.

DOI: https://doi.org/10.1038/s41409-026-02823-2
J Biol Chem. 2026 Mar 20. pii: S0021-9258(26)00260-7. [Epub ahead of print] 111390

Mesothelin Promotes Acute Myeloid Leukemia Progression through LYN-dependent Signaling.

Joshua R Faust, Darcy Hamill, E Anders Kolb, Alexandra M Stevens, Anilkumar Gopalakrishnapillai, Sonali P Barwe.

  Mesothelin (MSLN) is a glycosylphosphatidylinositol-anchored cell surface protein that is overexpressed in several solid tumors and in one-third of pediatric acute myeloid leukemia (AML) cases. It represents a validated immunotherapeutic target owing to its lack of expression in normal bone marrow. The function of MSLN in AML is unknown, but it is implicated to regulate adhesion in solid tumors through interaction with its only known binding partner, MUC16/CA125. This study uses CRISPR/Cas9 mutagenesis to generate knockout (KO) of MSLN in NOMO-1 and a MSLN-expressing patient-derived xenograft model to investigate its biological role in AML. We show that MSLN-KO cells proliferate slower, have reduced mitochondrial metabolism, are arrested in G1 cell cycle phase, adhere less to extracellular matrix in vitro and engraft slower in vivo. MSLN-KO cells also exhibit increased sensitivity to Ara-C and reduced extracellular matrix-mediated chemoprotection. Using an unbiased approach, we identify Src-family kinase member LYN, and guanine nucleotide-binding protein G(i) alpha subunit proteins, GNAI1, GNAI2, and GNAI3 as novel binding partners of MSLN in AML and show that pharmacological or genetic inhibition of LYN signaling restores NOMO-1 cell sensitivity to Ara-C. Together, these findings demonstrate that MSLN functions as an oncogenic driver in AML and reveal a previously unrecognized MSLN-LYN signaling axis, the therapeutic targeting of which may enhance responses to chemotherapy.

Keywords:  Acute myeloid leukemia; GPI-anchored protein; LYN; adhesion; cell proliferation; chemoresistance; mesothelin

DOI:  https://doi.org/10.1016/j.jbc.2026.111390
Life (Basel). 2026 Mar 06. pii: 428. [Epub ahead of print]16(3):

Autophagy and Lipid Metabolism as a Therapeutic Target for Overcoming Drug Resistance in Acute Myeloid Leukemia.

Seyed Mohammadreza Bolandi, Mahdi Pakjoo, Briandy Fernandez-Marrero, Amir Reza Boskabadi, Erfan Mohammadi Sephavand, Jamshid Sorouri Khorashad, Saeid Ghavami, Anna M Eiring.

  Acute myeloid leukemia (AML) remains a therapeutically challenging malignancy due to high relapse rates driven by leukemic stem cells (LSCs) and adaptive resistance mechanisms. Emerging evidence positions autophagy as a central regulator of AML pathobiology, exerting context-dependent effects that suppress leukemogenesis during disease initiation yet sustain LSC survival and chemoresistance in established AML. Mechanistically, autophagy integrates mitochondrial quality control, lipid droplet turnover, and metabolic rewiring to support oxidative phosphorylation, particularly under hypoxic bone marrow conditions. Lipophagy-driven fatty acid oxidation has emerged as a key metabolic vulnerability distinguishing LSCs from normal hematopoietic stem cells. Furthermore, non-coding RNAs critically modulate autophagy networks, reinforcing therapy resistance. Preclinical and clinical studies demonstrate that both inhibition and activation of autophagy may yield therapeutic benefit depending on genetic context, mutational landscape, and disease stage. We propose that integrating multi-omics approaches, particularly lipidomics, with artificial intelligence and machine learning will enable precise identification of autophagy-dependent AML subsets. Rational, biomarker-guided modulation of autophagy may overcome resistance while preserving normal hematopoiesis, offering a path toward personalized metabolic targeting in AML.

Keywords:  acute myeloid leukemia (AML); autophagy; cancer drug resistance; leukemia stem cells (LSCs); lipid metabolism; non-coding RNAs

DOI:  https://doi.org/10.3390/life16030428
Br J Haematol. 2026 Mar 17.

Chemotherapy-driven expression of WNT ligands in bone marrow stromal cells contributes to chemoresistance in acute lymphoblastic leukaemia.

Foteini Kalampalika, Amanda Jiménez-Pompa, Raúl Sánchez-Lanzas, Bela Patel, Miguel Ganuza.

  Despite recent advances, treatment outcomes for adults with acute lymphoblastic leukaemia (ALL) remain poor. Although patients often exhibit an initial favourable response to chemotherapy, with substantial clearance of tumour cells, most patients eventually relapse. This indicates the persistence of a chemoresistant ALL subpopulation capable of driving disease regeneration. Growing evidence implicates interactions between leukaemia cells and the bone marrow (BM) niche in this process. Our findings show that BM-derived mesenchymal stem cells (MSCs) and adipocytes (BMAds) promote chemotherapy resistance in ALL cells via activation of the wingless-related integration site (WNT) signalling pathway. Chemotherapy-treated co-cultures of MSCs/BMAds and ALL cells exhibited upregulation of several WNT ligands in the stromal compartment. Notably, pharmacological inhibition of WNT signalling abrogated the stromal-mediated chemoprotection and enhanced ALL cell apoptosis in vitro. In vivo, WNT inhibition in a p185BCR-ABLArf-/- B-ALL mouse model sensitised leukaemia cells to chemotherapy, delaying relapse and extending survival. Collectively, these results support the therapeutic potential of WNT inhibitors as a strategy to block the cross-talk between the BM stroma and leukaemic cells and reduce ALL chemoresistance.

Keywords:  WNT pathway; acute lymphoblastic leukaemia; bone marrow niche; chemoresistance

DOI:  https://doi.org/10.1111/bjh.70431
Blood. 2026 Mar 27. pii: blood.2025031102. [Epub ahead of print]

IGH::FENDRR and specific KRAS mutations define a novel B-ALL molecular subtype with poor chemotherapy response.

Sonja Bendig, Alina M Hartmann, Wiebke Wessels, Thomas Beder, Rathana Kim, Marie Passet, Qingsong Gao, Nadine Wolgast, Johanna M Horns, Leonardo Alves Santos, Katharina Iben, Fabio D Steffen, Loredana Cantoni, Britta Kehden, Guranda Chitadze, Axel Künstner, Hauke Busch, Beat Bornhauser, Jean-Pierre Bourquin, Thibaut Tl Leguay, Nicolas Boissel, Nicola Gökbuget, Ilaria Iacobucci, Charles G Mullighan, Emmanuelle Clappier, Claudia D Baldus, Monika Brüggemann, Lorenz Bastian.

Large scale sequencing efforts have defined up to 27 diagnostic entities in B-ALL, leaving few samples without subtype assignment. Extended genomic and transcriptomic profiling in routine diagnostics broadens the sample collection and holds the potential to identify novel B-ALL subtypes. By analyzing an aggregated set of 4,857 B-ALL patients from three cohorts, we identified a novel group of twenty cases (age 18-66 years, median: 34 years) characterized by a previously undescribed IGH::FENDRR rearrangement exclusive to this subtype (n=17/20), KRAS p.A146T/V/P mutations (n=17/20 vs. n=86/4,857; p<0.001) and distinct DNA-methylation/gene expression profiles, including overexpression of the lncRNA FENDRR and the transcription factor FOXF1 ('FOXF1/FENDRR') as well as JAK/STAT and RAS signaling signatures. A gene expression machine learning classifier identified FOXF1/FENDRR cases in two independent cohorts with high accuracy. Patients treated according to GMALL/GRAALL protocols showed very poor chemotherapy response with n=8/13 having induction failure or MRD ≥10-3 and n=8/12 remaining MRD positive after 1st consolidation / salvage. MRD-stratified intensification including blinatumomab (n=10) and/or allogenic stem cell transplantation (n=12) resulted in ongoing molecular remission in 13/16 cases. FOXF1/FENDRR patients represent a novel B-ALL subtype which might benefit from early immunotherapeutic treatment or targeted interventions.

DOI: https://doi.org/10.1182/blood.2025031102
Leukemia. 2026 Mar 24.

Flare of clonal hematopoiesis, TP53 expansion and prior melphalan drive post-CAR-T myeloid disorders in multiple myeloma.

Johannes Waldschmidt, David Fandrei, Judith S Hecker, Manja Meggendorfer, Marietta Truger, Franz Reinhard, Benjamin Shibru, Marion Högner, Anna Gebauer, Max Köppel, Heiko Müller, Johannes Jung, Daniel Teschner, Max S Topp, Anna Purcarea, Vladan Vučinić, Torsten Haferlach, Florian Bassermann, Uwe Platzbecker, Hermann Einsele, Claudia Haferlach, K Martin Kortüm, Klaus H Metzeler, Maximilian Merz, Katharina S Götze, Leo Rasche.

DOI: https://doi.org/10.1038/s41375-026-02941-2
Cell Death Discov. 2026 Mar 24.

Autophagy inhibition potentiates the antileukemic effect of FLT3 inhibitors and overcomes resistance in FLT3-ITD acute myeloid leukemia.

Manuela Albuquerque de Melo, Brunno Gilberto Santos de Macedo, Diego A Pereira-Martins, Antônio Bruno Alves-Silva, Natasha Peixoto Fonseca, Livia Bassani Lins de Miranda, Cleide Lucia Araújo Silva, Priscila Santos Scheucher, Jan Jacob Schuringa, João Agostinho Machado-Neto, Fabiola Traina.

Autophagy induction has recently emerged as a mechanism of resistance to FLT3 inhibitors (FLT3i) in patients with FLT3-ITD mutant acute myeloid leukemia (AML). Here, we assessed the molecular mechanisms of autophagy inhibition associated with FLT3i and its impact on cell survival and pharmacological resistance. In FLT3-ITD AML cell lines (MOLM13 and MV4-11), treatment with first- and second-generation FLT3i (midostaurin and quizartinib, respectively) induced autophagy. Combining FLT3i with autophagy inhibitors further decreased cell viability and increased cell apoptosis in both cell lines and in primary patient samples. Label-free quantification proteomics of MOLM13 cells revealed that RFC4 (Replication Factor C Subunit 4), an autophagy regulator linked to increased chemosensitivity, and GATD3/C21orf33 (Glutamine Amidotransferase Class 1 Domain Containing 3) proteins were upregulated only in the combined group, while 11 proteins mostly associated with chemoresistance were downregulated. In vivo, the combination of midostaurin and autophagy inhibition improved overall survival in MOLM13-transplanted mice. ATG5- (Autophagy Related 5) and ATG7-knockdown (Autophagy Related 7) increased sensitivity to first- and second-generation FLT3i in MOLM13 cells. To investigate the potential of autophagy inhibition in overcoming FLT3i resistance, we generated MV4-11 cells resistant to quizartinib (MV4-11QR). The resistant cell line exhibited higher basal levels of autophagy compared to the parental cell line. The combination of quizartinib and chloroquine demonstrated a synergistic effect in MV4-11QR cells and this effect was associated with greater inhibition of the FLT3 receptor compared to the monotherapies. Therefore, combining FLT3i with autophagy inhibition enhances the FLT3i antileukemic efficacy and overcomes pharmacological resistance.

DOI: https://doi.org/10.1038/s41420-026-03037-7
Br J Haematol. 2026 Mar 25.

Single-cell transcriptional consequences of leukaemogenic SETBP1 mutations.

Mi K Trinh, Nathaniel D Anderson, Matthew D Young, Holly J Whitfield, Conor Parks, Toochi Ogbonnah, Agnes Oszlanczi, Di Zhou, Emilia R Robertson, Angus Hodder, Rebecca Thomas, Karin Straathof, Stuart Adams, Jack Bartram, Nuala Summerfield, Sam Behjati.



Keywords:  SETBP1 mutation; Schinzel–Giedion syndrome; myelodysplastic leukaemia; single‐cell transcriptional dysregulation

DOI:  https://doi.org/10.1111/bjh.70452
Blood. 2026 Mar 24. pii: blood.2025032254. [Epub ahead of print]

FLT3-ITD scaffolds PKCι-STAT1 to drive noncanonical S727 phosphorylation and CD276-driven CD8+ T-cell exhaustion in AML.

Yun Wang, Shuzhao Chen, Shutong Liu, Zhijian Liang, Hailin Zheng, Chunhua Li, Qianqian Huang, Qi Liang, Ziang Zhu, Weida Wang, Yang Liang, Xiao-Jun Huang.

FLT3-ITD mutation is associated with poor prognosis in acute myeloid leukemia (AML), yet its kinase-independent mechanisms remain unclear. To investigate kinase-independent immunosuppressive mechanisms in FLT3-ITD AML, we integrated single-cell RNA sequencing from two public datasets and multiparameter flow cytometry data from 104 primary patient samples, identifying profound CD8+ T cell exhaustion as a hallmark of the FLT3-ITD immune microenvironment. Mechanistically, FLT3-ITD acts as a mutation-specific scaffold that assembles a ternary complex with PKCι and STAT1, as demonstrated by co-immunoprecipitation and intracellular colocalization. This complex enables PKCι-mediated phosphorylation of STAT1 specifically at serine 727 (S727), driving CD276 transcription independent of the canonical tyrosine 701 (Y701) site. Chromatin immunoprecipitation, electrophoretic mobility shift, promoter-reporter assays, and phosphosite-mutant constructs confirmed that S727 phosphorylation is necessary and sufficient for CD276 transactivation. Multiplex immunohistochemistry of patient bone marrow validated co-elevation of pS727-STAT1 and CD276 in FLT3-ITD blasts, accompanied by CD8+ T cell depletion. Functionally, CD276 upregulation induced profound CD8+ T cell exhaustion, characterized by reduced cytotoxicity, impaired proliferation, diminished IFN-γ production and elevated inhibitory checkpoints expression. Targeting CD276 restored CD8+ T cell function by 1.2-1.7-fold (cytotoxicity), 1.4-1.7-fold (proliferation), 1.5-1.8-fold (IFN-γ secretion) and 25.4%-67.6% (checkpoints expression) in ex vivo co-culture. In patient-derived xenograft models, co-treatment with FLT3i (quizartinib) and CD276-targeting agents led to 72.9%-80.4% tumor burden reduction and enhanced CD8+ T cell function, outperforming quizartinib monotherapy. These findings define a scaffolded PKCι-pS727-STAT1 signaling axis that promotes immune evasion in FLT3-ITD AML, supporting combined FLT3 and CD276 targeting as a promising translational strategy in this aggressive leukemia subtype.

DOI: https://doi.org/10.1182/blood.2025032254
Leukemia. 2026 Mar 26.

Synergizing hypomethylating agents with off-the-shelf CD70-targeted chimeric antigen receptor-engineered natural killer T cells for the treatment of acute myeloid leukemia.

Yan-Ruide Li, Xinyuan Shen, Yuning Chen, Yichen Zhu, Jie Huang, Caspian Oliai, Lili Yang.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by the uncontrolled expansion of undifferentiated myeloid precursors in the bone marrow. Hypomethylating agents (HMAs) such as azacitidine and decitabine can reverse abnormal DNA methylation, promote leukemic cell differentiation, and enhance immune recognition, yet relapse and therapeutic resistance remain major challenges. In this study, we found that long-term, low-dose HMA treatment upregulated CD70, NK receptor ligands, and CD1d on AML tumor cells, rendering them more susceptible to chimeric antigen receptor (CAR)-engineered invariant natural killer T (CAR-NKT) cell-mediated cytotoxicity. To exploit these features, we generated two types of CD70-targeting CAR-NKT cells: cord blood hematopoietic stem and progenitor cell (HSPC)-derived allogeneic CAR70-NKT (AlloCAR70-NKT) cells and peripheral blood mononuclear cell (PBMC)-derived CAR70-NKT (PBMCCAR70-NKT) cells. Both CAR70-NKT cell products exhibited potent cytotoxicity against AML cells and synergized with HMAs, while AlloCAR70-NKT cells demonstrated superior antitumor efficacy, multi-target recognition, and sustained expansion. In multiple xenograft models, AlloCAR70-NKT cells effectively killed AML tumors without inducing graft-versus-host disease, cytokine release syndrome, or long-term organ toxicity. These findings highlight AlloCAR70-NKT cells as a safe and powerful off-the-shelf immunotherapy that can synergize with HMAs to improve treatment outcomes for patients with AML.

DOI: https://doi.org/10.1038/s41375-026-02930-5
Br J Haematol. 2026 Mar 25.

Results from the prospective phase 2 multicentre UK PBSC haplo trial using PTCy pre- or post-stem cells.

Hugues deLavallade, William Wilson, Rachel Protheroe, Matthew Smith, Darren Edwards, Katie O'Donnell, Eleni Tholouli, Shankaranarayan Paneesha, Matthew Collin, Ben Uttenthal, David Irvine, MonMon Yee, Paul Tappenden, Panagiotis Kottaridis, John A Snowden, Steven Mackinnon, Antonio Pagliuca, Kavita Raj.

  This prospective phase 2 multicentre non-randomised parallel arm study of haploidentical peripheral blood stem cell (PBSC) transplantation with post-transplant cyclophosphamide (PTCy) recruited 77 patients: 50 received reduced-intensity conditioning (RIC) with PTCy post stem cell infusion while 27 underwent myeloablative conditioning (MAC) with PTCy given after lymphocyte but prior to infusion of CD34 selected stem cells. The primary end-point 1-year overall survival (OS) was 86% for RIC and 78% for MAC, meeting the pre-specified targets for efficacy. At 4 years, OS was 63% for RIC and 60% for MAC with low non-relapse mortality of RIC 18% and MAC 4%. Engraftment was faster in the MAC arm (median time to neutrophil and platelet engraftment 11 and 15 days; 21 and 24 days in the RIC arm). The economic analysis showed that MAC had higher initial transplant costs, RIC incurred greater post-transplant monitoring costs, resulting in higher overall costs (RIC £156 711, MAC £131 092). Quality of life (QoL) outcomes in both indicated significant post-transplant declines at 3 months but returned to baseline by 12 months. This study confirms the long-term safety of using PBSC with PTCy in haploidentical transplants, with a good quality of life and reasonable costs.

Keywords:  PTCy; haploidentical transplant

DOI:  https://doi.org/10.1111/bjh.70429
Expert Opin Pharmacother. 2026 Mar 26. 1-8

Tyrosine kinase inhibitors, chronic myeloid leukemia, and pregnancy: pharmacotherapeutic challenges and recommendations.

Fadi G Haddad, Elias Jabbour, Helen T Chifotides, Shereen Sakkal, Hagop Kantarjian.

   INTRODUCTION: The annual incidence of Philadelphia chromosome-positive chronic myeloid leukemia (CML) is 1 per 100,000 pregnancies. The management of CML during pregnancy poses challenges due to the teratogenicity risk associated with the BCR:ABL1 tyrosine kinase inhibitors (TKIs).
AREAS COVERED: In this review, we discuss the possible fetotoxicity of CML therapies during pregnancy, including TKIs and non TKI-based regimens and the treatment strategies for pregnant patients.
EXPERT OPINION: The diagnosis of CML during pregnancy is rare, and evidence guiding optimal management remains limited. Current recommendations categorize treatments into TKIs and non TKI-based therapies. All TKIs are not recommended during the first trimester due to their risk of teratogenesis, but imatinib and nilotinib may be cautiously used from Weeks 16-18 onward. Non-TKI therapies, such as hydroxyurea and interferon-α, are considered safe throughout pregnancy. Data on ponatinib and asciminib remain insufficient to allow the safe use of these agents during pregnancy. Future research should aim to improve treatment-free remission rates through novel agents and combination strategies to allow a higher proportion of younger patients to discontinue therapy. Clinicians should always counsel women on pregnancy risks during therapy while reassuring male patients of TKI safety when fathering children.

Keywords:  Chronic myeloid leukemia; imatinib; interferon-α; nilotinib; ponatinib; pregnancy; tyrosine kinase inhibitors

DOI:  https://doi.org/10.1080/14656566.2026.2651280
Cell Death Dis. 2026 Mar 24.

Dynamic epigenetic regulation of BCLAF1 splicing in acute myeloid leukemia.

Giulia Sgueglia, Crescenzo Massaro, Annamaria Muro, Ida Lettiero, Erika D'Agostino, Gregorio Favale, Nicla Simonelli, Nunzio Del Gaudio, Vincenzo Carafa, Tommaso De Marchi, Dante Rotili, Sergio Valente, Antonello Mai, Gianluca Sbardella, Mariacarla De Simone, Lucia Altucci, Carmela Dell'Aversana.

Dysregulation of alternative splicing is increasingly associated with cancer development and tumor progression. BCL2-associated transcription factor 1 (BCLAF1) is involved in a wide range of biological processes and it is continuously being investigated due to its intricate function in tumorigenesis and drug resistance. In acute myeloid leukemia (AML) cell lines, we identified two distinct, unbalanced isoforms of BCLAF1: the full-length isoform, which exhibits oncogenic properties, and the short-length isoform, which seems to act as a tumor suppressor. Treatment with specific epidrugs can re-establish the physiological balance of full- and short-length isoforms, restoring their correct equilibrium. Our results suggest the existence of a newly identified mechanism underlying the regulation of BCLAF1 splicing orchestrated, at least in part, by the interplay between HDAC1 and DNMT3A, and directly correlated with the healthy or cancerous state of hematopoietic cells. Our findings shed light on a novel regulatory axis in AML and highlight the potential of epidrugs to restore normal splicing patterns, paving the way for innovative therapies.

DOI: https://doi.org/10.1038/s41419-026-08594-4
Sci Adv. 2026 Mar 27. 12(13): eaea4059

A synergistic interaction between PRMT5 and LSD1 inhibitors in AML.

Nesteene Joy Param, Elisa Arceci, Francesco Fiorentino, Luca Pignata, Denis Torre, Nayeli Gutiérrez-Trejo, Jia Yi Fong, Pierre-Alexis Goy, Brenda Y Han, Chiara Lambona, Elisabetta Di Bello, Carola Castiello, Marco Barone, Megan Schwarz, Cheryl Arrowsmith, Koichi Ito, Peggy Scherle, Dave Keng Boon Wee, Steven Ndoye, Tommaso Tabaglio, Anand D Jeyasekharan, Manikandan Lakshmanan, Roberto Cirilli, Hansjörg Habisch, Tobias Madl, Andrea Mattevi, Sergio Valente, Antonello Mai, Ernesto Guccione.

Acute myeloid leukemia (AML) is a hematopoietic malignancy caused by abnormal proliferation and differentiation of blasts. PRMT5, a methyltransferase that catalyzes symmetric dimethylation of arginine (SDMA) residues, has been implicated in cancer stem cell homeostasis and shown to be a potential therapeutic target in AML. However, given the toxicity of complete PRMT5 inhibition, there is a need to identify effective synergistic therapies. Through a targeted screen of compounds that inhibit key nodes of PRMT5-regulated pathways, we identified a synthetic lethality between inhibition of PRMT5 and LSD1, a lysine demethylase known to affect AML blast differentiation. The two inhibitors broadly reshape the transcriptome of targeted cells and synergize to promote AML differentiation and eventually growth inhibition and apoptosis, in a p53-dependent manner. To leverage this synthetic lethal interaction, we generated new dual compounds to inhibit both enzymes and recapitulated the effects of the drug combination. Our results uncover an unexpected convergence of PRMT5- and LSD1-regulated targets, paving the way for new therapeutic opportunities.

DOI: https://doi.org/10.1126/sciadv.aea4059
Mol Cell. 2026 Mar 23. pii: S1097-2765(26)00138-3. [Epub ahead of print]

RNF25 confers mRNA damage tolerance by curbing activation of the integrated stress response.

Shubo Zhao, Chloe S Palma-Chaundler, Carla M Engel, Jacqueline Cordes, Daniel Nixdorf, Michael Y Luo, Selay Kaya, Aldwin Suryo Rahmanto, Diana van den Heuvel, Timur Mackens-Kiani, Pedro Weickert, Simon Lam, Vipul Gupta, Julia Philippou-Massier, Ivan Bagarić, Jonathan Bohlen, Graeme Hewitt, Martijn S Luijsterburg, Roland Beckmann, Petra Beli, Danny D Nedialkova, Christopher J Carnie, Marion Subklewe, Stephen P Jackson, Julian Stingele.

  Excessive RNA damage activates cellular stress responses, triggering cell death. However, pathways that negatively regulate RNA damage responses are largely uncharacterized. Using genetic screens, we find that the ubiquitin ligase RNF25 provides tolerance to RNA damage caused by the nucleoside analogue azacytidine, a chemotherapeutic agent used to treat acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Mechanistically, we show that azacytidine is incorporated into mRNA, where it causes lesions that stall elongating ribosomes, leading to cytotoxic activation of the GCN2-dependent integrated stress response (ISR). Furthermore, we establish that RNF25 prevents ISR hyperactivation by ubiquitylation of ribosomal protein eS31, thereby suppressing cell death upon azacytidine treatment. Our study reveals an mRNA damage tolerance mechanism that determines cellular survival in response to azacytidine, highlighting RNA damage-induced stress response as a potentially critical component of chemosensitivity in AML and MDS.

Keywords:  GCN1; GCN2; RNA damage; RNF25; acute myeloid leukemia; azacytidine; chemotherapy; integrated stress response; ribosome collisions; ubiquitylation

DOI:  https://doi.org/10.1016/j.molcel.2026.02.024
Nat Rev Genet. 2026 Mar 23.

Genetic influences on haematopoiesis.

Michael Poeschla, Vijay G Sankaran.

Haematopoiesis has long been a paradigm for understanding how human genetic variation can influence physiology in health and disease, ranging from the genetic characterization of Mendelian blood diseases to population-scale genomic studies of blood cell phenotypes and diseases. More recently, advances in single-cell genomics and variant-to-function mapping are enabling mechanistic insights into how genetic variation shapes blood cell development. Alongside inherited variation, the characterization of somatic mutations accumulating in haematopoietic stem cells during the lifespan has revealed clonal haematopoiesis as a ubiquitous evolutionary process, with heterogeneous clonal expansions impacting haematopoietic function and disease risk. Insights from genetic studies of haematopoiesis are translating into therapeutic applications, transforming treatment for monogenic blood disorders and promising broader applications. As methods continue to advance, haematopoiesis will remain central to understanding how genetic variation influences human biology, disease susceptibility and therapeutic response.

DOI: https://doi.org/10.1038/s41576-026-00947-1
Sci Transl Med. 2026 Mar 25. 18(842): eadt4859

LSD1 inhibition ameliorates congenital dyserythropoietic anemia type II.

Lei Yu, Yu Wang, Richard King, Greggory Myers, Kaiwen Deng, Beth McGee, Ann Friedman, Ginette Balbin-Cuesta, Zesen Lin, Claire Drysdale, Xiaofang Liu, Joseph C Min, Claire Kerpet, Yuanfang Guan, Patrick J Gallagher, Ayse Bilge Ozel, Aaron Robida, James Douglas Engel, Rami Khoriaty.

Congenital dyserythropoietic anemia type II (CDAII) is an autosomal recessive disease resulting from loss-of-function mutations in SEC23 homolog B (SEC23B). We have previously shown that increased expression of SEC23A, a paralogous protein for SEC23B, rescues the CDAII erythroid defect. Here, we generated a human erythroid cell line that expresses enhanced green fluorescent protein (eGFP) from the endogenous SEC23A locus and performed a small-molecule screen to identify compounds that increased SEC23A-eGFP abundance. The top compound passing all filters was an inhibitor of lysine-specific demethylase 1 (LSD1). We found that LSD1 inhibition with RN1 resulted in increased SEC23A expression in erythroid cells derived from human hematopoietic stem and progenitor cells (HSPCs) at doses that did not impair erythroid cell growth or differentiation and rescued the erythroid defect resulting from SEC23B deletion. Genetic down-regulation of LSD1 led to a marked increase in SEC23A mRNA expression in HSPC-derived erythroid cells. Deletion of Lsd1 in mouse erythroid cells resulted in increased Sec23a expression, and RN1 treatment ameliorated the erythroid defect observed in a CDAII mouse model. Mechanistically, we found that LSD1 occupied a sequence in the SEC23A promoter, repressing SEC23A transcription. Deletion of the promotor sequence occupied by LSD1 resulted in increased SEC23A expression and amelioration of CDAII. These findings highlight that LSD1 represses SEC23A transcription and that LSD1 inhibition results in de-repression of SEC23A expression and amelioration of the CDAII erythroid defect, suggesting promising therapeutic strategies for CDAII.

DOI: https://doi.org/10.1126/scitranslmed.adt4859
Mol Cancer Ther. 2026 Mar 17.

A bispecific anti-fluorescein x anti-CD3 T-cell engager in combination with fluoresceinated adaptors enables lysis of AML cells.

Laura G Volta, Celeste Gobbi, Christian Koch, Niclas Harrer, Mara Hofstetter, Monique Maurer, Florin Schneiter, Francesco Manfredi, Christian Pellegrino, Chiara F Magnani, Timm Schroeder, Dario Neri, Markus G Manz.

Tumor-targeting antibodies, antibody-drug conjugates, and radionuclide antibody conjugates are established therapeutic tools in clinical use. Beyond, bispecific T-cell engaging antibodies (TCEs) and chimeric antigen receptor (CAR) T-cells are becoming clinical standard-of-care in hemato-oncology and in some solid tissue neoplasia. To allow for on-off switching and targeting of multiple antigens, CAR T-cells designed to recognize tumor-bound adaptor molecules (adaptor-CAR T-cells) are now being investigated in clinical trials. We hypothesized that, like adaptor-CAR T-cells, a bispecific TCE, recognizing CD3ε on T-cells and fluorescein on tumor-bound adaptors, would be able to direct T-cells against target cells, potentially enabling multi-plexing. We here show that a newly generated single chain Fv-based anti-CD3 x anti-FITC construct (AdFITC-TCE) activates T-cells towards acute myeloid leukemia. Recognition of multiple targets through binding to fluoresceinated antibody constructs against CD33 and CD117 enables efficient tumor cell lysis in vitro. Moreover, we demonstrate that AdFITC-TCE plus fluoresceinated adaptors and T-cells inhibit acute myeloid leukemia cell growth in NSG mice in vivo with similar efficacy as AdFITC-CAR T-cells. Together, this data suggests that AdFITC-TCE, in combination with any given fluoresceinated binder, might be a versatile tool to activate T-cells, leading to respective target cell lysis.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-0985
Br J Haematol. 2026 Mar 23.

Leveraging paired germline and somatic analysis to improve the classification of DDX41 variants.

Andrew George, Elisabeth Rolf, Monika Domeradzka, Sara Ribeiro, Brittany Mills, April Hallett, Suzanne Macmahon, Paula Proszek, Ridwan Shaikh, Lina Yuan, Michael Hubank, Mikel Valganon Petrizan, Terri P McVeigh, Jamshid S Khorashad.

  Constitutional pathogenic variants in DDX41 predispose to myelodysplasia and acute myeloid leukaemia. Acquisition of subsequent somatic hits in the second allele is frequent, with notable recurrent variants at key hotspots. Sequencing of Deoxyribonucleic acid from blood/marrow of 239 patients with suspected/confirmed haematological malignancies at a single centre within a 4-year period identified 136 unique DDX41 variants. Among those with co-occurring somatic and likely/confirmed germline variants, 54.8% of likely/confirmed germline variants were pathogenic when classified according to current Cancer Variant Interpretation Group UK (CanVIG-UK) guidelines (incorporating American College of Medical Genetics [ACMG] criteria), while 45.2% were deemed variants of uncertain significance (VUS). Classification of variants as uncertain poses challenges, as it then calls into question the underlying aetiology of the malignancy, as well as the significance of any subsequent somatic DDX41 variants. As carrier relatives of suspected deleterious DDX41 variants will not usually be considered as donors for bone marrow transplantation, classification of variants of likely germline origin will have immediate treatment implications. Current ACMG and CanVIG-UK guidelines do not permit co-occurrence with recurrent somatic driver variants as evidence favouring pathogenicity, despite this being a convincing finding. This study proposes modifying certain rules as a basis for developing DDX41-specific guidance, as it will significantly impact decisions surrounding bone marrow transplantation.

Keywords:   DDX41 ; ACMG; CanVIG; MDS

DOI:  https://doi.org/10.1111/bjh.70411