bims-tremyl 2025-08-17 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2025–08–17
27 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Outcomes of adult patients with newly diagnosed IDH-mutated AML treated with intensive chemotherapy and venetoclax.
Oral decitabine and cedazuridine maintenance after haematopoietic stem-cell transplantation in very high-risk acute myeloid leukaemia or myelodysplastic syndrome (GFM-DACORAL-DLI): a multicentre, single-arm, phase 2 trial.
Exploiting an Epigenetic Resistance Mechanism to PI3 Kinase Inhibition in Leukemic Stem Cells.
Genetic variation reveals a homeotic long noncoding RNA that modulates human hematopoietic stem cells.
The oral CDK9 inhibitor voruciclib combined with venetoclax for patients with relapsed/refractory acute myeloid leukemia.
Impact of radiotherapy site, modality, and dose on subsequent clonal hematopoiesis.
NAMPT haploinsufficiency is a collateral lethal therapeutic vulnerability in high-risk myeloid malignancies with TP53 inactivation.
Venetoclax plus gilteritinib is effective in preclinical models of FLT3-mutant BCL11B-a lineage-ambiguous leukemia.
Lysine-specific demethylase 1 regulates hematopoietic stem cell expansion and myeloid cell differentiation.
Systematic evaluation of GAPs and GEFs identifies a targetable dependency for hematopoietic malignancies.
Clinical and molecular characterization of TP53-mutant acute lymphoblastic leukemia in adults.
Graft-versus-host disease is not associated with reduced incidence of relapse following haploidentical stem cell transplantation with post-transplant cyclophosphamide for acute lymphoblastic leukaemia: A study on behalf of the Acute Leukaemia Working Party of European Society for Blood and Marrow Transplantation.
FTO degrader impairs ribosome biogenesis and protein translation in acute myeloid leukemia.
Treatment-free remission in chronic myeloid leukaemia patients with accelerated phase or tyrosine kinase inhibitor therapy failure.
American College of Rheumatology Guidance Statement for Diagnosis and Management of VEXAS Developed by the International VEXAS Working Group Expert Panel.
Clonal hematopoiesis and inflammation predict hematologic toxicity and secondary myeloid malignancies after BCMA-directed chimeric antigen receptor T cell therapy.
Cathepsin D promotes acute myeloid leukemia progression through stabilization of the anti-apoptotic proteins.
Inflammatory signaling in the pathogenesis of acute myeloid leukemia.
The ALDH2/PolG2 axis enhances mitochondrial biogenesis via transcriptional regulation of Nrf2 and promotes chemotherapy resistance in acute myeloid leukaemia.
Vaccine-Educated T cells and a CD123 Bispecific T-Cell Engager for Treatment of Acute Myeloid Leukemia.
Engraftment and persistence of HBB base-edited hematopoietic stem cells in nonhuman primates.
White blood cell count as a powerful prognostic marker and treatment guide in paediatric acute myeloid leukaemia with NUP98 rearrangement.
Cell surface surprise: NPM1 is an immune therapy target for acute myeloid leukemia.
Allogeneic Transplant for CMML.
SUCLG1 deficiency-induced histone succinylation impairs oncogene expression in acute myeloid leukemia.
Platelets sequester extracellular DNA, capturing tumor-derived and free fetal DNA.
Unraveling the impact of crizotinib to promote megakaryopoiesis for alleviating thrombocytopenia in myelodysplastic neoplasms.

Leukemia. 2025 Aug 14.

Outcomes of adult patients with newly diagnosed IDH-mutated AML treated with intensive chemotherapy and venetoclax.

Jennifer Croden, Wei-Ying Jen, Jennifer Marvin-Peek, Lianchun Xiao, Ian M Bouligny, Sanam Loghavi, Gautam Borthakur, Naval G Daver, Hussein A Abbas, Koichi Takahashi, Koji Sasaki, Naveen Pemmaraju, Nicholas J Short, Danielle Hammond, Elias Jabbour, Lucia Masarova, Kelly S Chien, Ghayas C Issa, Guillermo Montalban-Bravo, Musa Yilmaz, Abhishek Maiti, Yesid Alvarado-Valero, Guillermo Garcia-Manero, Farhad Ravandi, Marina Y Konopleva, Hagop M Kantarjian, Tapan M Kadia, Courtney D DiNardo.

DOI: https://doi.org/10.1038/s41375-025-02733-0
Lancet Haematol. 2025 Aug 07. pii: S2352-3026(25)00172-3. [Epub ahead of print]

Oral decitabine and cedazuridine maintenance after haematopoietic stem-cell transplantation in very high-risk acute myeloid leukaemia or myelodysplastic syndrome (GFM-DACORAL-DLI): a multicentre, single-arm, phase 2 trial.

Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) and the Groupe Francophone des Myélodysplasies (GFM)

BACKGROUND: The combination of a hypomethylating agent with donor lymphocyte infusion as maintenance therapy after haematopoietic stem-cell transplantation (HSCT) in acute myeloid leukaemia and myelodysplastic syndrome might reduce the risk of relapse. We aimed to evaluate the activity and safety of oral decitabine and cedazuridine (ASTX727) as maintenance after allogeneic HSCT in patients with acute myeloid leukaemia or myelodysplastic syndrome at very high risk of relapse post-transplantation.
METHODS: We conducted a multicentre, single-arm, phase 2 study (GFM-DACORAL-DLI) at 12 centres in France. We enrolled patients aged 18-70 years with an Eastern Cooperative Oncology Group performance status of 0-2, without contraindication for HSCT, and with very high-risk disease (poor or very poor prognosis according to the revised International Prognostic Scoring System for myelodysplastic syndrome, adverse risk according to the 2017 European LeukemiaNet classification for acute myeloid leukaemia; unfavourable genetics; and acute myeloid leukaemia post-myelodysplastic syndrome or post-myeloproliferative neoplasm, or relapsing less than 2 years after complete response). Patients were included 5-45 days before transplantation. ASTX727 was orally administered at escalating doses (100 mg cedazuridine plus 35 mg decitabine starting at 1 day per cycle and increasing to 3 days) from day 40 post-HSCT, up to ten cycles. Donor lymphocyte infusion was recommended when patients had no contraindication after cycle 4. The primary endpoint was disease-free survival at 1 year after HSCT, assessed in the first 28 enrolled patients treated with ASTX7277. Safety was assessed in all participants who received at least one course of ASTX727. This study was registered with ClinicalTrials.gov (NCT04857645); enrolment is complete but follow-up is ongoing.
FINDINGS: Between Sept 28, 2021, and March 1, 2023, 59 patients were screened and 51 patients underwent allogeneic HSCT (median age 62·0 years [IQR 56·5-65·0]; 22 [43%] female, 29 [57%] male). 34 patients received maintenance treatment with ASTX727; seven of them received at least one donor lymphocyte infusion. 14 (41%) patients completed the ten cycles. Median follow-up was 12·6 months (IQR 10·3-14·3). Among the first 28 enrolled patients treated with ASTX727, disease-free survival at 1 year after HSCT was 70·4% (95% CI 55·1-89·9). The most frequent grade 3 or worse adverse events were haematological, occurring in 25 (74%) of 34 patients (21 [62%] neutropenia, eight [24%] thrombocytopenia, four [12%] anaemia). Serious adverse events occurred in 14 (41%) of 34 patients, and were haematological in eight patients and gastrointestinal in three patients. One treatment-related death, due to thrombocytopenia, occurred.
INTERPRETATION: ASTX727 could be a potential treatment option after HSCT in patients with acute myeloid leukaemia or myelodysplastic syndrome at very high risk of relapse. Further investigation is warranted to establish the efficacy and safety of this therapeutic approach.
FUNDING: Taiho Oncology and Astex Pharmaceuticals.

DOI: https://doi.org/10.1016/S2352-3026(25)00172-3
bioRxiv. 2025 Jul 15. pii: 2025.07.11.663968. [Epub ahead of print]

Exploiting an Epigenetic Resistance Mechanism to PI3 Kinase Inhibition in Leukemic Stem Cells.

Shira G Glushakow-Smith, Imit Kaur, Simone Sidoli, Shayda Hemmati, Ellen Angeles, Taneisha Sinclair, Samarpana Chakraborty, Aaliyah Battle, Kristina Ames, Swathi-Rao Narayanagari, Rotila Hyka, Mark Soto, Melissa Tracy, Jayaram Vankudoth, Seiya Kitamura, Linde Miles, Ulrich Steidl, Aditi Shastri, Amit Verma, Kira Gritsman.

Acquired non-genetic resistance mechanisms to existing therapies contribute to poor outcomes for acute myeloid leukemia (AML) patients, and inability to target leukemic stem cells (LSCs) can lead to relapse. To overcome these challenges, we tested whether LSCs have dependencies on PI3 kinase (PI3K). We found that LSCs are susceptible to isoform-selective targeting of PI3K and are particularly dependent on the P110 alpha isoform of PI3K. We discovered that PI3K inactivation leads to dynamic changes in EZH2/PRC2 function in leukemic cells, and we uncovered downregulation of EZH2 protein levels as a resistance mechanism in response to PI3K inhibition. We found that PI3K inhibition in AML cells can lead to compensatory upregulation of EZH1, and that EZH1 knockdown can sensitize AML cells to PI3K inhibition. We leveraged this resistance mechanism by combining a PI3K inhibitor with an EZH1/2 dual inhibitor, which successfully overcomes the acquired resistance and leads to sustained targeting of AML cells ex vivo and in murine AML and PDX models in vivo. This study identifies a promising novel therapeutic regimen for targeting LSCs in AML.

DOI: https://doi.org/10.1101/2025.07.11.663968
bioRxiv. 2025 Jul 16. pii: 2025.07.16.664824. [Epub ahead of print]

Genetic variation reveals a homeotic long noncoding RNA that modulates human hematopoietic stem cells.

Peng Lyu, Gaurav Agarwal, Chun-Jie Guo, Tianyi Ye, Chen Weng, Mateusz Antoszewski, Samantha Joubran, Alexis Caulier, Michael Poeschla, Vijay G Sankaran.

The HOXA gene locus coordinates body patterning, hematopoiesis, and differentiation. While studying blood phenotype-associated variation within the HOXA locus, we identified a genetic variant, rs17437411, associated with globally reduced blood counts, protection from blood cancers, and variation in anthropometric phenotypes. We find that this variant disrupts the activity of a previously unstudied antisense long non-coding RNA (lncRNA) located between HOXA7 and HOXA9 , which we have named HOTSCRAMBL . The HOTSCRAMBL variant disrupts lncRNA function and reduces human hematopoietic stem cell (HSC) self-renewal. Mechanistically, HOTSCRAMBL enables appropriate expression and splicing of HOXA genes in HSCs, most notably HOXA9 , in an SRSF2-dependent manner. Given the critical role of HOXA gene expression in some blood cancers, we also demonstrate that HOTSCRAMBL variation or deletion compromises HOXA -dependent acute myeloid leukemias. Collectively, we show how insights from human genetic variation can uncover critical regulatory processes required for effective developmental gene expression.

DOI: https://doi.org/10.1101/2025.07.16.664824
Blood Neoplasia. 2025 Aug;2(3): 100108

The oral CDK9 inhibitor voruciclib combined with venetoclax for patients with relapsed/refractory acute myeloid leukemia.

Yesid Alvarado-Valero, Rachel J Cook, Shira N Dinner, Michael Keng, Kebede H Begna, Nathalie Javidi-Sharifi, Sameem Abedin, Monzr M Al Malki, Vijaya Raj Bhatt, Prabhu Rajagopalan, Min Tang, Sandra E Wiley, Richard G Ghalie, Matthew S Davids.

The antiapoptotic protein myeloid cell leukemia 1 (Mcl-1) promotes cell survival in acute myeloid leukemia (AML), and its overexpression is associated with resistance to venetoclax. Voruciclib, an oral cyclin-dependent kinase 9 inhibitor, indirectly decreases Mcl-1 protein expression and has synergistic activity with venetoclax in AML preclinical models. We hypothesized that voruciclib in combination with venetoclax would induce responses in patients with AML with disease progression after venetoclax therapy. This dose-escalation study evaluated voruciclib administered on days 1 to 14 of 28-day cycles with venetoclax daily. The study enrolled 41 adult patients with AML after failure of previous standard therapies. Patients had a median of 2 (range, 1-7) previous lines of therapy, 19 patients (46%) had ≥3 previous lines of therapy, and 39 (95%) had previous venetoclax. No dose-limiting toxicities were reported in 7 dose levels evaluated. The most common adverse events were nausea (34%), febrile neutropenia (32%), diarrhea (22%), dyspnea (22%), hypokalemia (22%), and thrombocytopenia (22%). Antileukemic activity was observed in 10 (24%) patients, including 3 with complete marrow remission and 7 with stable disease lasting ≥3 months. We observed a rebound of circulating blasts during the 14 days of single-agent venetoclax dosing in 40% of evaluable patients. Mcl-1 protein expression and RNA polymerase II Ser-2 phosphorylation decreased on voruciclib. Overall, the combination of voruciclib with venetoclax was tolerable in patients with relapsed/refractory AML, had antileukemic activity, and showed on-target effects in heavily pretreated patients with disease progression after venetoclax. This trial was registered at www.ClinicalTrials.gov as #NCT03547115.

DOI: https://doi.org/10.1016/j.bneo.2025.100108
Blood Adv. 2025 Aug 12. pii: bloodadvances.2025016376. [Epub ahead of print]

Impact of radiotherapy site, modality, and dose on subsequent clonal hematopoiesis.

Alexander G Goglia, Griffen Mustion, Leslie A Modlin, Ross L Levine, Kelly L Bolton, Lior Z Braunstein.

DOI: https://doi.org/10.1182/bloodadvances.2025016376
Blood Neoplasia. 2025 Aug;2(3): 100119

NAMPT haploinsufficiency is a collateral lethal therapeutic vulnerability in high-risk myeloid malignancies with TP53 inactivation.

Madhavi D Senagolage, Hunter Z Blaylock, Saira Khan, Sarah J Skuli, Martin P Carroll, Megan E McNerney.

Monosomy 7 (-7) and deletions of chromosome arm 7q (del(7q)) are prevalent high-risk cytogenetic abnormalities that often co-occur with del(17p) (harboring TP53). To identify novel targeted therapies based on specific vulnerabilities in high-risk myeloid malignancies, we investigated druggable, chromosome 7-encoded essential genes that are monoallelically deleted in the context of -7/del(7q), that is, collateral lethal genes. By mining genome-wide CRISPR-Cas9 screen data sets, we identified nicotinamide phosphoribosyltransferase (NAMPT) on 7q22.3 as a specific susceptibility in 81.5% of -7/del(7q) malignancies. Human acute myeloid leukemia (AML) cell lines with partial loss of NAMPT and primary samples from patients with -7 AML demonstrated heightened sensitivity to the NAMPT inhibitor KPT-9274 compared to control samples. Notably, NAMPT inhibitors were equally effective in NAMPT-deficient samples with TP53 loss. Furthermore, combining NAMPT and poly (ADP-ribose) polymerase (PARP) inhibitors, which augment DNA damage, resulted in synergistic therapeutic effects in NAMPT-deficient AML cells. These findings indicate that NAMPT heterozygosity is a therapeutic vulnerability in high-risk myeloid malignancies with -7/del(7q) and recommend NAMPT levels as a biomarker for NAMPT inhibitor sensitivity. This study also establishes a data-driven framework for identifying collateral lethal genes in cancers with recurrent chromosomal deletions.

DOI: https://doi.org/10.1016/j.bneo.2025.100119
Blood. 2025 Aug 14. pii: blood.2025028985. [Epub ahead of print]

Venetoclax plus gilteritinib is effective in preclinical models of FLT3-mutant BCL11B-a lineage-ambiguous leukemia.

Lindsey E Montefiori, Ilaria Iacobucci, Qingsong Gao, Jamila Moore, William C Wright, Huimei Wei, Pradyumna Baviskar, Surbhi Sona, Hongjian Jin, Amit Budhraja, Josi Lott, Qi Zhang Tatarata, Zhongshan Cheng, Tanya M Khan, Emily A Backhaus, Melissa D Johnson, Cyrus M Mehr, Burgess B Freeman, Laura J Janke, Torsten Haferlach, Paul Geeleher, Paul E Mead, Marina Y Konopleva, Joseph T Opferman, Charles G Mullighan.

Aberrant activation of BCL11B ("BCL11B-a") defines a subtype of lineage ambiguous leukemias with T-lymphoid and myeloid features, co-occurring activating FLT3 mutations, and a stem/progenitor immunophenotype and gene expression profile. As with other lineage ambiguous leukemias, optimal treatment is unclear and there are limited targeted therapeutic options. Here, we investigated the efficacy of BCL-2 and FLT3 inhibition with venetoclax and gilteritinib, respectively, in preclinical models of BCL11B-a leukemia. Despite variation in response to single agent therapies, the combination of venetoclax plus gilteritinib (VenGilt) was highly effective in all models evaluated. BH3 profiling suggested that resistance to venetoclax monotherapy was due to the tumor-intrinsic dependence on additional BCL-2 family proteins prior to drug treatment. Longitudinal single cell RNA-seq analysis identified mitochondrial pathways and a pro-lymphoid gene expression signature as potential drivers of rare cell survival on VenGilt therapy. These data support clinical evaluation of venetoclax in combination with gilteritinib in BCL11B-a lineage ambiguous leukemias.

DOI: https://doi.org/10.1182/blood.2025028985
Cell Death Dis. 2025 Aug 15. 16(1): 619

Lysine-specific demethylase 1 regulates hematopoietic stem cell expansion and myeloid cell differentiation.

Hans Felix Staehle, Christoph Koellerer, Anne Marie Staehle, Jana Schulze, Philipp Eble, Anja Müller, Franziska Zell, Judith M Müller, Florian Perner, Aya Attia, Jan-Philipp Mallm, Olga Pozdnyakova, Karsten Rippe, Benedikt Brors, Lars Feuerbach, Charles D Imbusch, Eric Metzger, Roland Schüle, Heike L Pahl, Jonas S Jutzi.

The lysine-specific demethylase 1 (LSD1) regulates hematopoietic stem cell differentiation and has been identified as a therapeutic target in hematological disorders. LSD1 demethylates mono and dimethylated histones 3 at lysine 4 and 9. In addition, it acts as a scaffold for the formation of chromatin-modifying complexes that regulates the transcription of myeloid-lineage-specific genes in complex with GFI1, a transcriptional repressor. While both enzymatic and non-enzymatic functions of LSD1 have been well defined, the relative importance of these two functions in hematopoiesis remains incompletely understood. Here, we investigated the contribution of enzymatic and non-enzymatic functions of LSD1 to myelopoiesis. We show that myeloid differentiation is independent of the enzymatic functions of LSD1 but requires the non-enzymatic, scaffolding function, which directs GFI1 binding to target sequences. In the absence of the LSD1 protein, GFI1 DNA binding is diminished, and myeloid cell differentiation arrests at an immature, myelomonocytic-like cell stage, which overexpresses Prtn3. We provide functional data implicating Prtn3 as an effector of the stem cell expansion and myeloid maturation block caused by the loss of LSD1.

DOI: https://doi.org/10.1038/s41419-025-07951-z
Cancer Discov. 2025 Aug 12.

Systematic evaluation of GAPs and GEFs identifies a targetable dependency for hematopoietic malignancies.

Pu Zhang, Zhendong Cao, Xiangyu Pan, Yuqiao Liu, Cynthia Castro, Won Jun Kim, Takeshi Fujino, Jennifer Lewis, Jahan Rahman, Sanam Shahid, Jasmine Um, Erin Burns, Bingyi Chen, Winson Cai, Juliana Ortiz-Pacheco, Zhuoning Li, Mara Monetti, Christopher R Vakoc, Anthony F Daniyan, Omar Abdel-Wahab, Junwei Shi.

GAPs (GTPase-activating proteins) and GEFs (guanine nucleotide exchange factors) play key roles in cancer development, but their large number and potential redundancy have limited systematic evaluation. Here we perform unbiased genetic screens to identify GAPs and GEFs with cancer- and lineage-specific requirements, as well as dual perturbation screens to dissect functionally relevant interactors of GAPs and GEFs. Application to primary acute myeloid leukemia (AML) patient specimens uncovers the GAP ARHGAP45 as a targetable dependency shared across cancers of hematopoietic origin while being dispensable in normal hematopoiesis. We demonstrate that targeting ARHGAP45-expressing cells can be achieved through TCR-CAR T cells directed at an ARHGAP45-encoded minor histocompatibility antigen and that pharmacologic targeting of GAPs required upon ARHGAP45 depletion augments ARHGAP45-directed cell therapies. These studies provide a resource for probing oncogenic and druggable regulators of GTPases and strategies to target a GAP that represents a shared dependency across blood cancers.

DOI: https://doi.org/10.1158/2159-8290.CD-25-0299
Blood Cancer J. 2025 Aug 14. 15(1): 138

Clinical and molecular characterization of TP53-mutant acute lymphoblastic leukemia in adults.

Ethan J Harris, Diren Arda Karaoglu, Madina Sukhanova, Yasmin Abaza, Theodoros Karantanos, Ann-Kathrin Eisfeld, Clare Anderson, Chenyu Lin, Yenny A Moreno Vanegas, Talha Badar, Alexander Coltoff, Todd C Knepper, Neval Ozkaya, Hamed Rahmani Youshanlouei, Sinan Cetin, Anand A Patel, Adam S DuVall, Michael W Drazer, Peng Wang, Melissa Tjota, Jeremy P Segal, Girish Venkataraman, Sandeep Gurbuxani, Jason X Cheng, Daniel A Arber, Richard A Larson, Olatoyosi Odenike, Jonathan Webster, Bijal Shah, Wendy Stock, Caner Saygin.

TP53-mutant acute lymphoblastic leukemia (ALL) in adults is a high-risk subtype with poor outcomes, yet its molecular landscape and clinical implications remain incompletely defined. In this multi-institutional study of 830 adult ALL patients treated at eight academic centers between 2010 and 2024, we demonstrated that TP53 mutations are independent predictors of inferior overall survival in both B-ALL (median, 1.9 vs 5 years) and T-ALL (1.6 vs 9.5 years), irrespective of age, biologic disease subtype, or therapy. Genomic profiling revealed that >90% of TP53 mutations were DNA-binding domain missense variants, frequently co-occurring with hypodiploidy in B-ALL and NOTCH1/FBXW7 mutations in T-ALL. Unlike myeloid malignancies, biallelic TP53 mutations did not worsen outcomes, and variant type (missense vs truncating) did not influence survival. TP53-mutant B-ALL exhibited higher CD20 positivity than TP53-wild type B-ALL (65% vs 31%) but had inferior responses to conventional chemotherapy. Novel immunotherapies (e.g., inotuzumab/blinatumomab) or venetoclax-containing combination regimens improved remission rates, yet relapses were common, often with CD19/CD20/CD22 loss (triple-negative) or acquisition of new mutations. Allogeneic transplantation in first remission trended toward survival benefit (median, 3.3 vs 2.2 years). These findings underscore TP53-mutant ALL as a distinct, chemo-resistant entity necessitating tailored approaches, with antigen escape highlighting challenges of immunotherapy durability.

DOI: https://doi.org/10.1038/s41408-025-01350-5
Br J Haematol. 2025 Aug 14.

Graft-versus-host disease is not associated with reduced incidence of relapse following haploidentical stem cell transplantation with post-transplant cyclophosphamide for acute lymphoblastic leukaemia: A study on behalf of the Acute Leukaemia Working Party of European Society for Blood and Marrow Transplantation.

Avichai Shimoni, Christophe Peczynski, Myriam Labopin, Alida Dominietto, Mariya Koc, Mutlu Arat, Johanna Tischer, Simona Sica, Zafer Gülbas, Gerard Socié, Didier Blaise, Pietro Pioltelli, Hakan Ozdogu, Jan Vydra, Fabio Ciceri, Arnon Nagler, Mohamad Mohty.

  The graft-versus-leukaemia effect (GVL) is closely associated with graft-versus-host disease (GVHD) after human leucocyte antigen (HLA)-matched allogeneic stem-cell transplantation (SCT) in acute lymphoblastic leukaemia (ALL). However, there are no data on this association following haploidentical SCT (haploSCT) with post-transplant cyclophosphamide (PTCy). We assessed the impact of acute and chronic GVHD on haploSCT outcomes in 516 adult ALL patients. The cumulative incidence of acute GVHD grade II-IV and III-IV, chronic GVHD and extensive chronic GVHD was 33.3%, 11.7%, 35.3% and 11.8% respectively. The 2-year relapse incidence (RI), non-relapse mortality (NRM) and overall survival (OS) were 27.1%, 17.3% and 64.4% respectively. The time-dependent hazard ratios (HRs) of acute GVHD grade II, grade III-IV, limited and extensive chronic GVHD associated with RI were 0.92 (95% confidence interval [CI] 0.58-1.48, p = 0.74), 0.57 (95% CI, 0.27-1.22, p = 0.15), 1.06 (95% CI, 0.62-1.82, p = 0.83) and 0.95 (95% CI, 0.42-2.17, p = 0.91) respectively. Acute GVHD grade III-IV and extensive chronic GVHD were associated with higher NRM (hazard ratio [HR] 1.95 [95% CI, 1.09-3.48, p = 0.002] and 3.3 [95% CI, 1.41-7.73, p = 0.006]) and reduced OS (HR 1.91 [95% CI, 1.07-3.39, p = 0.03] and 3.27 [95% CI, 1.4-7.66, p = 0.006]) respectively. In conclusion, acute and chronic GVHD are not statistically associated with reduced RI after haploSCT with PTCy in ALL. Higher GVHD grades are associated with higher NRM and lower OS.

Keywords:  acute lymphoblastic leukaemia; graft‐versus‐host disease; graft‐versus‐leukaemia effect; haploidentical transplantation; post‐transplant cyclophosphamide

DOI:  https://doi.org/10.1111/bjh.70101
Sci Adv. 2025 Aug 15. 11(33): eadv7648

FTO degrader impairs ribosome biogenesis and protein translation in acute myeloid leukemia.

Wenlong Li, Yutao Zhao, Dong Wu, Zhenhua Chen, Ying Qing, Fan Yang, Fei Ji, Linda Zhang, Lillian Sau, Jianjun Chen, Chuan He.

Targeting ribosome biogenesis and protein translation has emerged as a promising avenue for cancer therapy. The fat mass and obesity-associated protein (FTO), an RNA N6-methyladenosine (m6A) eraser, has been identified as an oncogenic factor in acute myeloid leukemia (AML). Here, we present the development of an FTO degrader that selectively degrades FTO in AML cells, demonstrating superior efficacy both in vitro and in vivo. We confirmed that FTO degradation increases m6A modifications on mRNAs associated with ribosome biogenesis, promoting their YTHDF2-mediated decay. This disruption of ribosome biogenesis and protein translation contributes to the inhibition of AML progression. Our findings highlight this FTO degrader as a valuable tool compound for elucidating the functional roles of FTO in cancer and as a potential foundation for the development of selective anticancer therapies.

DOI: https://doi.org/10.1126/sciadv.adv7648
Br J Haematol. 2025 Aug 13.

Treatment-free remission in chronic myeloid leukaemia patients with accelerated phase or tyrosine kinase inhibitor therapy failure.

Mengyao Yuan, Yanli Zhang, Bingcheng Liu, Li Zhou, Yu Zhu, Zhenling Li, Shaolei Zang, Zhenfang Liu, Weiming Li, Qian Jiang.

  We studied 60 chronic myeloid leukaemia (CML) patients with a prior history of accelerated phase (AP) including de novo AP (n = 19) and transformation to AP (n = 4), or tyrosine kinase inhibitor (TKI) therapy failure in the chronic phase (CP, n = 37), who discontinued TKI therapy. Median interval from diagnosis with AP or TKI therapy failure to achieving a deep molecular response (DMR) was 19 months (interquartile range [IQR], 9-30 months). Median TKI treatment and DMR duration were 108 months (IQR, 72-137 months) and 59 months (IQR, 39-87 months) respectively. At a median follow-up of 21 months (IQR, 11-36 months) after TKI discontinuation, 19 (31%) patients lost the major molecular response (MMR). The 3-year probability of a sustained MMR was 59% (95% confidence interval [CI], [45%, 78%]). In the multivariable analyses, age at discontinuation <32 years (hazard ratio [HR] = 4.1 [1.3, 12.7], p = 0.014) and BCR::ABL1 >0.1% at 12 months on TKI therapy (reference, ≤0.1%; HR = 3.9 [1.4, 11.5], p = 0.011) were significantly associated with a higher probability of MMR loss after TKI discontinuation. CML patients with a history of AP or TKI therapy failure may achieve successful treatment-free remission after an adequate TKI therapy duration and a sustained DMR.

Keywords:  accelerated phase; chronic myeloid leukaemia; therapy failure; treatment‐free remission; tyrosine kinase inhibitor

DOI:  https://doi.org/10.1111/bjh.70080
Arthritis Rheumatol. 2025 Aug 11.

American College of Rheumatology Guidance Statement for Diagnosis and Management of VEXAS Developed by the International VEXAS Working Group Expert Panel.

International VEXAS working group, and with endorsement of EuroBloodNet, the European Reference Network in Rare Hematological Diseases

OBJECTIVE: Vacuoles E1 enzyme X-linked autoinflammatory somatic syndrome (VEXAS) is a recently identified rare genetic disorder associated with somatic mutations in the UBA1 gene. VEXAS presents with a combination of inflammatory and hematologic manifestations, leading to increased morbidity and mortality.
METHODS: Given the variability in disease presentation and the limited number of studies to date, no clinical documents currently exist to provide guidance to health care providers about the management of VEXAS. To address this gap, we formed an international multidisciplinary panel of VEXAS experts.
RESULTS: Through formalized meetings and a voting process, the group developed consensus clinical guidance considerations for the management of VEXAS. These considerations offer practical advice on several key topics: (1) clinical features of VEXAS, (2) UBA1 screening methods, (3) the diagnosis of myelodysplastic syndromes (MDSs) in patients with VEXAS, and (4) prognosis and management. The aim is to provide expert guidance on which patients to test, how to test for VEXAS, how to approach MDS in the context of VEXAS, and considerations for management.
CONCLUSION: This work marks the first formal international consensus guidance for VEXAS and is intended to be used as a resource for clinicians seeking to understand the disease and its management.

DOI: https://doi.org/10.1002/art.43287
Clin Cancer Res. 2025 Aug 13.

Clonal hematopoiesis and inflammation predict hematologic toxicity and secondary myeloid malignancies after BCMA-directed chimeric antigen receptor T cell therapy.

Zachary M Avigan, Jerrel Catlett, Saoirse Bodnar, Darren Pan, Adolfo Aleman, Tianxiang Sheng, Erin Moshier, Adriana C Rossi, Shambavi Richard, Gurbakhash Kaur, Joshua Richter, Larysa J Sanchez, Cesar Rodriguez, Hearn Jay Cho, Shafinaz Hussein, Christian Salib, Lewis R Silverman, Sundar Jagannath, Samir Parekh, Santiago Thibaud.

PURPOSE: Chimeric antigen receptor T cells (CAR-T) have demonstrated remarkable efficacy in multiple myeloma, but prolonged hematologic toxicity remains a common adverse event, and secondary myeloid malignancies are a significant safety concern.
EXPERIMENTAL DESIGN: We evaluated 213 myeloma patients treated with B-cell maturation antigen (BCMA)-directed CAR-T at our center to characterize clinical, inflammatory, and myeloid clonal features associated with hematologic toxicity.
RESULTS: Patients with persistent grade ≥3 neutropenia or thrombocytopenia at day 100 (19%) had shorter progression-free survival (p=.0003) and overall survival (p<.0001), and amongst those with continued remissions, 64% developed prolonged high-grade cytopenias beyond one year. While baseline inflammation is a risk factor for hematologic toxicity, underlying clonal hematopoiesis (CH) modulated this risk, and the combination of CH and elevated ferritin was highly predictive of delayed recovery (adjusted HR 0.38, p=.006). Serum cytokine analysis in patients with delayed myeloid recovery showed a signature of persistent inflammation and endothelial dysfunction. Finally, 9% developed secondary myeloid diseases, including 5% with high-grade myelodysplastic syndrome (MDS) requiring therapy a median of 14.5 months post-CAR-T. MDS was associated with clonal expansion of underlying TP53-mutated CH from a median variant allele frequency of 3.4% pre-CAR-T to 44.0%. While patients with baseline TP53-mutated CH exhibited clonal evolution and a high incidence of MDS (67%), other CH mutations did not show similar expansion after CAR-T (p>.99).
CONCLUSIONS: This study underscores the impact of hematologic toxicity and CH on BCMA CAR-T outcomes and suggests a potential role of CAR-T in influencing TP53 clonal dynamics and myeloid disease development.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-1587
Cell Death Dis. 2025 Aug 12. 16(1): 611

Cathepsin D promotes acute myeloid leukemia progression through stabilization of the anti-apoptotic proteins.

Huimin Jiang, Yongjian Wang, Churan Wang, Lu Yang, Shujuan Wang, Feng Wang, Situ Xue, Zhuan Zhang, Haigen Fu, Ting Dong, Jian Yuan, Zhuorong Li, Ke Li.

Cathepsin D (CTSD) is a lysosomal aspartic protease that plays vital roles in regulating the properties of solid tumors, including proliferation, apoptosis, migration, metastasis, and angiogenesis. However, the function of CTSD in haematological malignancies remains largely elusive. Here we show that CTSD is highly expressed in acute myeloid leukemia (AML) and that high CTSD expression is associated with unfavourable prognosis. Knockdown of CTSD in AML cells inhibits cell proliferation and anti-apoptotic activity. Mechanistically, CTSD decreased the expression of the E3 ubiquitin ligase TRIM21, which mediates the ubiquitination and degradation of anti-apoptotic proteins BCL2, BCL-XL, and MCL1. Inhibition of CTSD expression via genetics or the small-molecule inhibitor N-8 decreases the protein levels of BCL2, BCL-XL, and MCL1 through accelerating their degradation. N-8 shows significant efficacy in eradicating AML in both venetoclax-sensitive and -resistant models. Collectively, our study reveals the role of CTSD in leukemia progression and highlights targeting CTSD as a potential therapeutic strategy in AML.

DOI: https://doi.org/10.1038/s41419-025-07949-7
Hemasphere. 2025 Aug;9(8): e70188

Inflammatory signaling in the pathogenesis of acute myeloid leukemia.

Artemis Margrith Baumann, Jana Maria Ellegast.

Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of hematopoietic stem and progenitor cells and the most common malignant myeloid disorder in adults. Extensive research has elucidated the broad spectrum of biological mechanisms contributing to the development of AML and specifically characterized a variety of genetic alterations initiating and defining the disease. However, the role of inflammation in the pathogenesis of AML remains relatively unexplored; indeed, studies on the contribution of inflammatory signaling to disease initiation in myeloid malignancies have only recently gained attention, marking an emerging area of research. AML has the highest incidence in the elderly, where inflammation plays an even greater role. A granular understanding of inflammatory processes driving leukemogenesis thus promises to guide therapeutic strategies for a patient population where outcomes remain dismal. This review offers a comprehensive synthesis of the current knowledge on the role of inflammatory signaling in AML pathogenesis. It discusses the role of inflammation from premalignant states through malignant transformation, dissecting phenotypic, correlative studies from mechanistic evidence. We thereby highlight questions requiring further research to exploit the translational potential of therapies targeting inflammatory signaling and to address challenges with current immune-modulating treatments. A particular focus is placed on assessing the role of inflammation in the interplay with genetic events as established factors in disease initiation and progression to clarify the current understanding of inflammatory signaling in AML pathogenesis.

DOI: https://doi.org/10.1002/hem3.70188
Cell Death Dis. 2025 Aug 13. 16(1): 616

The ALDH2/PolG2 axis enhances mitochondrial biogenesis via transcriptional regulation of Nrf2 and promotes chemotherapy resistance in acute myeloid leukaemia.

Xiuying Hu, Tianzhen Hu, Shuyun Cao, Li Jiang, Yan Zhou, Qin Fang, Jishi Wang.

Although patients with acute myeloid leukaemia (AML) initially respond to conventional treatments, many patients die from AML progression and relapsed/refractory (RR) disease. Eradicating AML thus remains therapeutically challenging. In this study, we found a strong expression of aldehyde dehydrogenase 2 (ALDH2) and increased mitochondrial biosynthesis in samples from patients with drug-resistant AML, and these changes were strongly associated with poor prognosis and recurrence of AML. We examined the clonogenic capacity, growth and apoptosis of AML cells, as well as mitochondrial DNA expression and reactive oxygen species production. Our results revealed that chemotherapeutic agents triggered the activation of NF-E2-related factor 2 (Nrf2) and promoted high expression of ALDH2, mediating the compensatory activation of mitochondrial respiration and resistance to chemotherapeutic agents in RR AML cells. Nrf2 promoted mitochondrial respiration by activating ALDH2 expression and stabilising the expression of DNA polymerase-gamma2 (PolG2) in mitochondria. Inhibition of the Nrf2-ALDH2/PolG2 pathway reduced AML metabolic fitness and oxidative phosphorylation levels, highlighting the key role of this pathway in promoting cell survival. Nrf2 inhibition reduced the translation of ALDH2, induced a unique mitochondrial stress response and inhibited mitochondrial biosynthesis in AML cells. Importantly, tumours in an in vivo xenograft model were sensitive to combined Nrf2 and ALDH2 inhibition. Given the role of the Nrf2-ALDH2/PolG2 pathway in the progression of AML, inhibition of this pathway may prevent disease relapse/resistance and promote sensitisation to chemotherapy.

DOI: https://doi.org/10.1038/s41419-025-07927-z
Blood Adv. 2025 Aug 14. pii: bloodadvances.2024015449. [Epub ahead of print]

Vaccine-Educated T cells and a CD123 Bispecific T-Cell Engager for Treatment of Acute Myeloid Leukemia.

Jessica Liegel, Dina Stroopinsky, Giulia Cheloni, Dimitra Karagkouni, Myrna Nahas, Yuling Ma, Daniela Torres, Isabella Saldarriaga, Shuoshuo Wang, Antonella Arruda de Amaral, Athanasios Ploumakis, Sean G Clohessy, Joseph Abirached, Lina Bisharat, Paula G Fraenkel, Ozlem Yildirim, Hélène Bonnevaux, Stephane Guerif, Katie Rallis, Georges Chedid, Donald Kufe, Ioannis S Vlachos, David E Avigan, Jacalyn Rosenblatt.

T cell engager (TCE) therapy has demonstrated significant therapeutic efficacy in patients with hematologic malignancies. Durable responses have been linked with T cell clonotypic expansion. We hypothesized that combining vaccine educated T cells (veTc) that induce the expansion of leukemia specific T cells would enhance efficacy of TCE through greater induction of tumor specific immunity. In the present study, we explored a TCE targeting human CD123 on myeloid leukemia cells in conjunction with T cells stimulated by an autologous DC/AML fusion vaccine in a murine xenograft model. We demonstrated that the combination of CD123 T cell engager (SAR440234) and veTc boosted tumor specific T cell immunity and enhanced anti-leukemia effect in vitro. Furthermore, in vivo SAR440234 and veTc combination treatment fully eradicated leukemia engraftment outperforming SAR440234 in conjunction with uneducated T cells. This effect was associated with an increase in cytotoxic T cell subsets and clonotypic expansion. Thus, the combination of T cell engager with adoptive T cell transfer of vaccine educated T cells is a novel approach that merits further investigation in clinical trials.

DOI: https://doi.org/10.1182/bloodadvances.2024015449
Sci Transl Med. 2025 Aug 13. 17(811): eadn2601

Engraftment and persistence of HBB base-edited hematopoietic stem cells in nonhuman primates.

Stefan Radtke, Emily Fields, Kyle Swing, Greta Kanestrom, Jonathan S Yen, Dnyanada Pande, Mark R Enstrom, Olivier Humbert, Mitchell J Weiss, David R Liu, Gregory A Newby, Hans-Peter Kiem.

Sickle cell disease (SCD) is caused by a single nucleotide change in the β-globin gene that adenine base editors can convert to the nonpathogenic Makassar β-globin variant. Here, we evaluated the long-term efficiency and off-target editing potential of autologous Makassar base editing in three rhesus macaques as a step toward human translation. Base editing of CD34+CD90+ hematopoietic stem cells (HSCs) at the Makassar locus reached greater than 60% efficiency using a bystander nucleotide as a proxy for the sickle cell target in cells from healthy macaques. No impact on myeloid and erythroid colony formation was seen, and clonal analysis revealed that >90% of HSCs were edited, >20% with biallelic editing. After transplantation of autologous gene-edited HSCs, all three macaques rapidly recovered neutrophils, red blood cells, and platelets with stable editing of 25.6%, on average, observed across nucleated blood cells. Similarly, the bone marrow stem cell compartment maintained over 20% of cells harboring mono- or biallelic edits. Off-target editing was assessed at over 900 candidate sites, with editing observed at eight sites, but no selection for or impact of these edits was observed throughout engraftment. These data support further translation of base editing of autologous HSCs for the treatment of patients with SCD.

DOI: https://doi.org/10.1126/scitranslmed.adn2601
Br J Haematol. 2025 Aug 14.

White blood cell count as a powerful prognostic marker and treatment guide in paediatric acute myeloid leukaemia with NUP98 rearrangement.

Hui Shi, Wenjing Shu, Yu Tao, Xueming Jia, Yali Shen, Hua Yang, Yang Xun, Daniel Tomas Baptista-Hon, Hua You.

  NUP98-rearranged paediatric acute myeloid leukaemia (NUP98-r pAML) has an extremely poor prognosis, and the impact of clinical parameters and therapeutic schemes on its outcomes remains unclear. We conducted a retrospective study of the largest pAML cohort (1779 patients) and found that NUP98-r pAML has the worst prognosis among all subtypes. Furthermore, we identified white blood cell (WBC) count as the sole predictor of overall survival (OS) in NUP98-r pAML patients and validated its adverse prognostic impact in both external paediatric and adult cohorts. NUP98-r pAML patients were categorized into low-risk (WBC count ≤150 × 109/L) and high-risk (WBC count >150 × 109/L) groups based on WBC levels. Haematopoietic stem cell transplantation (HSCT) significantly improved OS and reduced the cumulative incidence of relapse (CIR) in the high-risk group but not in the low-risk group. Bortezomib significantly increased OS in NUP98::NSD1 patients within the low-risk group, and the combination of bortezomib and HSCT significantly enhanced OS in the entire NUP98-r pAML cohort. CD33 antibody (Gemtuzumab ozogamicin, GO) is not recommended for the entire NUP98-r pAML patients. In summary, WBC count is a pivotal marker for risk stratification and treatment decision-making in NUP98-r pAML patients.

Keywords:  NUP98 rearrangement; acute myeloid leukaemia; prognosis; treatment; white blood cell count

DOI:  https://doi.org/10.1111/bjh.70096
Hemasphere. 2025 Aug;9(8): e70193

Cell surface surprise: NPM1 is an immune therapy target for acute myeloid leukemia.

Hansen J Kosasih, Charles E de Bock.

DOI: https://doi.org/10.1002/hem3.70193
Curr Hematol Malig Rep. 2025 Aug 11. 20(1): 10

Allogeneic Transplant for CMML.

Nico Gagelmann, Nihar Desai.

PURPOSE OF REVIEW: Chronic myelomonocytic leukemia (CMML) is a rare hematologic malignancy at the intersection of myelodysplastic (MDS) and myeloproliferative neoplasms, predominantly affecting older adults. Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative option, yet its application is limited by the advanced age and comorbidities of most patients. Recent classification updates and refined prognostic tools, particularly molecularly integrated models like CPSS-Mol have enhanced patient stratification and informed transplant timing. The aim of this review is to highlight the evolving landscape of CMML management, with a focus on the role of allo-HCT.
RECENT FINDINGS: Novel studies patients demonstrated that individualized transplant timing significantly improved life expectancy. Optimizing transplant outcomes hinges on several factors:managing pretransplant splenomegaly, choosing appropriate debulking strategies, selecting optimal donors, and tailoring conditioning regimens. New data favor treosulfan-based and thiotepa-busulfan regimens for their favorable toxicity and relapse profiles. Post-transplant, strategies like post-transplant cyclophosphamide (PTCy) for GVHD prophylaxis and emerging approaches to minimal residual disease (MRD) monitoring offer additional refinements in patient management. While no MRD studies are CMML-specific, extrapolation from MDS supports its role in relapse prediction. Innovative therapies, including hypomethylating agent combinations, venetoclax, targeted inhibitors, and immunotherapies are under active investigation, with potential to improve pre- and post-transplant outcomes. Advancements in molecular classification, dynamic prognostic tools, and therapeutic strategies are reshaping the CMML treatment paradigm. Personalized approaches that integrate genetic risk, patient fitness, and disease characteristics are enabling more effective transplant strategies, with the ultimate goal of extending survival and improving quality of life in this complex and historically difficult-to-treat malignancy.

DOI: https://doi.org/10.1007/s11899-025-00754-1
Cell Rep. 2025 Aug 12. pii: S2211-1247(25)00918-0. [Epub ahead of print]44(8): 116147

SUCLG1 deficiency-induced histone succinylation impairs oncogene expression in acute myeloid leukemia.

Mengqing Gao, Minhui Shi, Hao Ding, Lei Xu, Na Zhao, Li Wang, Shujuan Huang, Hui Jiang, Ekaterina Bourova-Flin, Jianqing Mi, Saadi Khochbin, Domenico Iuso, Xiaoyu Zhu.

  Mitochondria-driven histone lysine succinylation is emerging as a critical signaling system that links cellular metabolism to the pathogenesis of diseases, including cancer. Here, we report that a global increase in protein/histone succinylation is associated with mitochondrial tricarboxylic acid cycle defects in acute myeloid leukemia (AML). Depletion of the succinyl-coenzyme A (CoA) synthetase alpha subunit SUCLG1 causes protein/histone hypersuccinylation in leukemia cells, which impairs cell proliferation and leukemia progression in xenograft models. Mechanistically, increased histone succinylation, which could compete with acetylation, attenuates the interaction of the bromodomain-containing protein 4 (BRD4) bromodomain with chromatin, hence disrupting BRD4-mediated leukemogenic gene transcription and restoring BRD4-dependent fine-tuned gene regulatory circuits. Our study uncovers the crucial role of metabolism-controlled histone succinylation in cancer development and highlights it as an innovative therapeutic approach.

Keywords:  BRD4; CP: Cancer; CP: Metabolism; SUCLG1; acute myeloid leukemia; histone succinylation

DOI:  https://doi.org/10.1016/j.celrep.2025.116147
Science. 2025 Aug 14. 389(6761): eadp3971

Platelets sequester extracellular DNA, capturing tumor-derived and free fetal DNA.

Lauren Murphy, Jeanne Inchauspé, Giampiero Valenzano, Pamela Holland, Nikolaos Sousos, Hayley L Belnoue-Davis, Rong Li, Natalie J Jooss, Camelia Benlabiod, Eleanor Murphy, Zohar Etzioni, Emelie Shepherd, Lucy Denly, Sujata Biswas, Lin Chen, Jennifer O'Sullivan, Michael P Rimmer, Abdullah O Khan, Christina Simoglou Karali, Nadia Nasreddin, Ian S Hitchcock, Milka Koupenova, Skirmantas Kriaucionis, Jim R Hughes, Eric O'Neill, Manu Vatish, Paul Rees, Simon Leedham, Michael Desborough, Adam J Mead, Benjamin Schuster-Böckler, Christopher D Gregory, Bethan Psaila.

Platelets are anucleate blood cells vital for hemostasis and immunity. During cell death and aberrant mitosis, nucleated cells release DNA, resulting in "cell-free" DNA in plasma (cfDNA). An excess of cfDNA is deleterious. Given their ability to internalize pathogen-derived nucleic acids, we hypothesized that platelets may also clear endogenous cfDNA. We found that, despite lacking a nucleus, platelets contained a repertoire of DNA fragments mapping across the nuclear genome. We detected fetal DNA in maternal platelets and cancer-derived DNA in platelets from patients with premalignant and cancerous lesions. As current liquid biopsy approaches utilize platelet-depleted plasma, important genetic information contained within platelets is being missed. This study establishes a physiological role for platelets that has not previously been highlighted, with broad translational relevance.

DOI: https://doi.org/10.1126/science.adp3971
Leukemia. 2025 Aug 14.

Unraveling the impact of crizotinib to promote megakaryopoiesis for alleviating thrombocytopenia in myelodysplastic neoplasms.

Hiroki Kobayashi, Yuta Komizo, Nanami Watanabe, Yu Miyata, Yoshiya Ohnuma, Yasushige Kamimura-Aoyagi, Kanako Yuki, Yoshihiro Hayashi, Minoru Yoshida, Yuka Harada, Hironori Harada.

Current therapeutic options for myelodysplastic neoplasms (MDS)-associated thrombocytopenia are limited. Megakaryocyte maturation might be an innovative therapeutic strategy because its dysregulation profoundly contributes to MDS pathogenesis. Here, we identified crizotinib, a clinically approved anti-cancer drug for anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer, as a potent inducer of megakaryocyte maturation. We demonstrated that crizotinib effectively induced polyploidization to increase the platelet-producing capacity of megakaryocytes derived from an MDS murine model and MDS patients by targeting Aurora kinases rather than its canonical targets, ALK/ROS1/c-MET. Importantly, crizotinib administration substantially ameliorated thrombocytopenia in our preclinical model. Our findings underscore the remarkable potential of crizotinib for drug repurposing and offer a novel therapeutic strategy for MDS patients with thrombocytopenia facing health-related quality of life concerns.

DOI: https://doi.org/10.1038/s41375-025-02729-w