Leukemia最新文献

{"title":"Clinical and transcriptomic characterization of patients with chronic lymphocytic leukemia harboring t(14;19): an ERIC study.","authors":"Andrea Visentin,Enrico Gaffo,Moritz Fürstenau,Kerry A Rogers,Baliakas Panagiotis,Chenghua Cui,Cecelia Miller,Claudia Haferlach,Karla Plevova,David Oscier,Zadie Davis,Florence Nguyen-Khac,Eleonora Roncaglia,Gian Matteo Rigolin,Anastasia Athanasiadou,Fanny Baran-Marszak,Alberto Valiente,Maria José Terol,Pau Abrisqueta,Blanca Espinet,Anna Puiggros,Annalisa Martines,Laura Bonaldi,Francesca Romana Mauro,Lydia Scarfò,Thomas Chatzikonstantinou,Eugen Tausch,Karl-Anton Kreuzer,Arnon Kater,Francesc Bosch,Michael Doubek,Panagiotis Panagiotidis,Olga Kalashnikova,Federica Frezzato,Giulia Calabretto,Valeria Ruocco,Silvia Orsi,Alessandro Cellini,Francesco Angotzi,Andrea Serafin,Shuhua Yi,Barbara Eichhorst,Jennifer A Woyach,Antonio Cuneo,Paolo Ghia,Kostas Stamatopoulos,Livio Trentin,Stefania Bortoluzzi","doi":"10.1038/s41375-025-02755-8","DOIUrl":"https://doi.org/10.1038/s41375-025-02755-8","url":null,"abstract":"In chronic lymphocytic leukemia (CLL), the role of complex karyotype (CK) for prognostic stratification remains a topic of debate, and the impact of specific cytogenetic abnormalities is still unclear. This study aims to investigate the clinical and biological features of CLL with t(14;19)(q32;q13) (tCLL) involving the BCL3 gene. Patients with tCLL were younger and more commonly presented unmutated IGHV gene, subset #8 stereotypy, trisomy of chromosome 12, and complex karyotype than other patients without t(14;19) (oCLL). The presence of t(14;19) was associated with a shorter time to treatment and overall survival compared to oCLL. Gene expression analysis revealed a unique transcriptome profile in tCLL, characterized by the upregulation of BCL3 and the activation of B-cell receptor, PI3K-Akt. Conversely, apoptosis-related pathways were suppressed in tCLL. While the BTK gene was upregulated, the BCL2L11 gene, coding for the pro-apoptotic protein BIM, was downregulated. Notably, patients with tCLL were characterized by a trend (p = 0.058) for a longer time to the next treatment with BTK inhibitors (BTKi) compared to those treated with a venetoclax-based (Ven-based) regimen. We underscore the adverse outcomes of tCLL, its distinct molecular features and gene expression patterns. Therefore, our data suggest that identifying tCLL could help tailor therapeutic approaches.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"29 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-dimensional analysis of adult acute myeloid leukemia cross-continents reveals age-associated trends in mutational landscape and treatment outcomes (Acute Myeloid Leukemia Cooperative Group & Alliance for Clinical Trials in Oncology).","authors":"Monica Cusan,Karilyn Larkin,Deedra Nicolet,Vindi Jurinovic,Krzysztof Mrózek,Aarif M N Batcha,Maja Rothenberg-Thurley,Stephanie Schneider,Cristina Sauerland,Dennis Görlich,Utz Krug,Wolfgang E Berdel,Bernhard J Woermann,Wolfgang Hiddemann,Jan Braess,Karsten Spiekermann,Philipp A Greif,James S Blachly,Alice S Mims,Christopher J Walker,Michael C Walker,Christopher C Oakes,Shelley Orwick,Andrew J Carroll,William G Blum,Bayard L Powell,Jonathan E Kolitz,Joseph O Moore,Robert J Mayer,Richard A Larson,Richard M Stone,John C Byrd,Klaus H Metzeler,Tobias Herold,Ann-Kathrin Eisfeld","doi":"10.1038/s41375-025-02644-0","DOIUrl":"https://doi.org/10.1038/s41375-025-02644-0","url":null,"abstract":"The outcome of patients with acute myeloid leukemia (AML) worsens with increasing age. Dichotomization into \"younger\" and \"older\" patients is clinically routine and often dictates treatment options. We aimed to delineate whether molecular genetic features and/or outcome measures support assorting patient populations by age, including division into \"younger\" and \"older\" groups. We analyzed 2823 adult AML patients enrolled onto frontline chemotherapy-based clinical protocols of two cooperative study groups from USA and Germany who were profiled molecularly via targeted sequencing platforms. Frequencies of gene mutations and cytogenetic findings were depicted in 5-year age increments. Clinical outcomes of 2756 AML patients were analyzed with respect to molecular features, genetic-risk groups and age. Age-associated distributions of gene mutations and cytogenetic abnormalities were similar in both cohorts. There was almost linear shortening of overall survival with increasing age among all patients (P < 0.001) and within 2022 European LeukemiaNet-defined genetic-risk groups, with survival decreasing as age increased (favorable-risk, P < 0.001; intermediate-risk, P < 0.001; adverse-risk, P < 0.001). Although mutational profiles and outcomes of the youngest patients differed from those of older patients, there was no age cut-off identifying \"younger\" and \"older\" patients. These findings support more age-associated flexibility for drug approval and trial eligibility.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"90 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epitranscriptomic advances in normal and malignant hematopoiesis.","authors":"Maria Eleftheriou,James Russell,Konstantinos Tzelepis","doi":"10.1038/s41375-025-02765-6","DOIUrl":"https://doi.org/10.1038/s41375-025-02765-6","url":null,"abstract":"RNA modifications, collectively termed the epitranscriptome, constitute a dynamic layer of post-transcriptional regulation that governs RNA splicing, stability, localization, translation, and decay. In the hematopoietic system, these chemical marks influence stem cell fate, lineage specification, immune surveillance, and malignant transformation through context-dependent regulation of mRNA, tRNA, rRNA, and non-coding RNAs. Here, we focus on RNA modifications and editing events with emerging mechanistic and translational relevance in normal and malignant hematopoiesis, highlighting those implicated in stem cell dynamics, leukemic progression, and therapeutic resistance. Specifically, we discuss N⁶-methyladenosine (m⁶A), 5-methylcytosine (m⁵C), N⁷-methylguanosine (m⁷G), N⁴-acetylcytidine (ac⁴C), pseudouridine (Ψ), adenosine-to-inosine (A-to-I) editing, and RNA glycosylation. Particular attention is given to enzymes such as METTL3, METTL1, ADAR1, and NAT10, whose dysregulation sustains leukemic stem cell programmes, promotes immune evasion, and confers treatment resistance. With the first-in-class METTL3 inhibitor STC-15 now in early-phase clinical trials in solid tumours (NCT05584111, NCT06975293), and additional RNA-modifying enzyme inhibitors advancing preclinically, these pathways are emerging as therapeutically tractable, including in hematological cancers. Furthermore, integrating epitranscriptomic profiles into genomic risk frameworks may also improve disease stratification, minimal residual disease (MRD) monitoring, and the identification of targetable vulnerabilities. Together, these insights position RNA modifications as central to blood cancer biology and support their integration into next-generation diagnostic, prognostic, and therapeutic strategies.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The endogenous T cell landscape is reshaped by CAR-T cell therapy and predicts treatment response in multiple myeloma.","authors":"Julia Frede,Julia C Poller,Kayleen Shi,Hannah Stuart,Noori Sotudeh,Claire Havig,Klothilda Lim,Caroline R M Wiggers,Eugene Y Cho,Tushara Vijaykumar,Jianlin Liu,Johannes M Waldschmidt,Monica S Nair,Praveen Anand,Valeriya Dimitrova,Anna Montanaro,Andrew J Yee,Nikhil C Munshi,Kenneth C Anderson,Nathan Martin,Shari M Kaiser,Marc-Steffen Raab,Noopur S Raje,Birgit Knoechel,Jens G Lohr","doi":"10.1038/s41375-025-02766-5","DOIUrl":"https://doi.org/10.1038/s41375-025-02766-5","url":null,"abstract":"While most patients initially respond to CAR-T cell treatment, responses often are not durable and subsequent lines of immunotherapy show diminishing success. In this study, we investigated the co-evolutionary dynamics between CAR-T cells and the immune microenvironment in myeloma patients undergoing anti-BCMA CAR-T cell therapy at single-cell resolution. Our findings highlight the transformative impact of CAR-T cell treatment on the endogenous T cell landscape. We identify a novel transitional CD8 + T cell population that is predictive of poor treatment outcomes. The emergence of this population coincides with the depletion of the endogenous T cell repertoire and compositional evolution of functional T cell subsets. These changes in the endogenous T cell compartment induced by CAR-T cell therapy may contribute to inadequate immune capacity and tumor control. Our findings highlight the potential of targeting TIM3/GAL9 interactions to mitigate T cell exhaustion, apoptosis and lack of persistence, offering promising avenues for optimizing T cell-based cancer immunotherapies. We provide a framework for assessing and manipulating the 'mileage' of the immune system as predictive marker and therapeutic opportunity to prevent repeated immunotherapies from becoming increasingly less successful, even when targeting distinct antigens.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"54 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Longitudinal single-cell analysis reveals treatment-resistant stem and mast cells with potential treatments for pediatric AML.","authors":"Denis Ohlstrom, Mojtaba Bakhtiari, Hope Mumme, Marina Michaud, Alejandro De Janon Gutierrez, Deborah DeRyckere, Katherine E Ferguson, Frank Chien, William Pilcher, Sarthak Satpathy, Sean Jordan, Douglas Graham, Swati Bhasin, Manoj Bhasin","doi":"10.1038/s41375-025-02773-6","DOIUrl":"https://doi.org/10.1038/s41375-025-02773-6","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clonal evolution and apoptosis resistance in myelodysplastic neoplasms and acute myeloid leukemia under treatment: insights from integrative longitudinal profiling.","authors":"Paolo Mazzeo,Sarah Mae Penir,Evgenii Shumilov,Sebastian Wolf,Björn Häupl,Katharina Markus,Katayoon Shirneshan,Katharina Rittscher,Elzbieta Brzuszkiewicz,Enver Aydilek,Hannes Treiber,Thomas Oellerich,Christina Ganster,Detlef Haase,Raphael Koch","doi":"10.1038/s41375-025-02756-7","DOIUrl":"https://doi.org/10.1038/s41375-025-02756-7","url":null,"abstract":"Treatment of high-risk Myelodysplastic Neoplasms (hr-MDS) and (secondary) Acute Myeloid Leukemia (AML) remains a clinical challenge. The combination of azacitidine and venetoclax (aza/ven) may improve treatment outcomes, but still fails in a significant fraction of patients. We established a single-center collection of longitudinal samples from patients with MDS and AML/sAML and performed comprehensive genetic, proteomic and functional apoptosis profiling to identify biomarkers and targetable escape mechanisms to aza/ven. Baseline genetic characterization (n = 55) identified high-risk genetic alterations, while longitudinal analyses (n = 268, mean 8.7 [3-20] timepoints) revealed distinct genetic profiles of clonal evolution. Functional BH3-profiling at treatment initiation identified heterogeneous dependencies on BCL-2 family members. Notably, high BCL-2 dependence correlated with genetic response to aza/ven and improved overall survival, whereas increased BCL-xL dependence was associated with resistance. We further identified patterns of acquired resistance, with loss of apoptotic priming and shifts in anti-apoptotic dependencies contributing to treatment failure. BH3 profiling revealed functional shifts toward MCL-1 and/or BCL-xL in individual cases, suggesting potential therapeutic targets to overcome resistance. In vitro, BCL-xL inhibition effectively counteracted resistance in increased BCL-xL dependence cases. In summary, we characterized treatment-associated clonal evolution in MDS and AML, providing insights into clinical response, disease progression and potential individualized therapeutic strategies.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"24 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Suppression of Rho-associated kinase 1 (ROCK1) promotes human hematopoietic stem cell expansion by attenuating mitochondrial fission","authors":"Xuepeng Wang, Baskar Ramdas, Ramesh Kumar, Ji Zhang, Reuben Kapur","doi":"10.1038/s41375-025-02770-9","DOIUrl":"https://doi.org/10.1038/s41375-025-02770-9","url":null,"abstract":"Ex vivo expansion of hematopoietic stem cells (HSCs) is limited by mitochondrial stress-induced loss of stemness. To identify protective mechanisms resembling the hypoxic bone marrow niche, we performed single-cell transcriptomics on hypoxia-collected HSCs, revealing significant downregulation of Rho-associated kinase 1 (ROCK1). This observation suggested ROCK1 as a potential regulator of HSC homeostasis. We tested this by genetically or pharmacologically inhibiting ROCK1 with shRNA or Y27632, which reduced mitochondrial reactive oxygen species, mitochondrial mass, and membrane potential while promoting expansion of phenotypic HSCs (Lin⁻CD34⁺CD38⁻CD45RA⁻CD49f⁺CD90⁺). Mechanistically, ROCK1 inhibition attenuated DRP1-mediated mitochondrial fission by decreasing p-DRP1(Ser616) and increasing p-DRP1(Ser637), thereby reducing mitochondrial fragmentation. Additionally, ROCK1 inhibition elevated BCL2 expression and reduced active Caspase-3 levels, indicating suppressed apoptosis. Limiting dilution transplants demonstrated a fourfold increase in functional HSC frequency following ROCK1 inhibition, with enhanced long-term engraftment in secondary recipients. Our findings identify ROCK1 as a critical regulator of mitochondrial dynamics in HSCs and provide a mechanistic basis for targeting ROCK1 to enhance functional HSC expansion, offering a promising strategy to improve outcomes in HSC transplantation by mimicking hypoxic niche signals ex vivo.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"42 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Granulocyte abundance and maturation state at diagnosis predicts treatment-free remission in CML","authors":"Mikko Purhonen, Mikael Tatun, Katariina Luukkainen, Kevin Hung, Henri Sundquist, Oda Tafjord, Stina Söderlund, Shady Adnan-Awad, Anni Dohlen, Johanna Heikkinen, Perttu Koskenvesa, Sanna Siitonen, Satu Mustjoki, Naranie Shanmuganathan, Coral Bryce, Signe Danielsson, Henrik Hjorth-Hansen, Ulla Olsson-Strömberg, Takashi Kumagai, Shinya Kimura, David M. Ross, Oscar Brück","doi":"10.1038/s41375-025-02769-2","DOIUrl":"https://doi.org/10.1038/s41375-025-02769-2","url":null,"abstract":"<p>Treatment-free remission (TFR) has become a therapeutic objective for selected chronic-phase chronic myeloid leukemia (CP CML). However, no standardized biomarker is yet in clinical use. In this multi-center study, we explored the potential of bone marrow (BM) cytomorphology given its global accessibility and integral role in clinical diagnostics. We included diagnostic BM aspirate samples of 113 CP CML patients from seven clinical sites having attempted first TKI discontinuation. We digitized cytomorphological slides into 100x-magnified high-resolution images and analyzed these with deep learning-based image analysis. We profiled the BM cytomorphological fingerprint of CP CML patients and recapitulated the known granulocytic predominance and reduction of lymphoid, monocytic and erythroid cells in comparison to an extensive cohort of 942 control BM samples. We discovered neutrophil abundance and granulocytic maturation to associate with sustained TFR. We confirmed these visually and demonstrated their independent impact over known clinical factors. Our study underlines the potential of computational BM cytomorphology to identify novel clinical biomarkers and suggests that granulocytic expansion and maturation at diagnosis could reflect intrinsic disease pathology influencing TFR maintenance.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"36 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Downregulation of MICA/MICB improves cell persistence and clinical activity of NKG2DL CAR T-cells in patients with relapsed or refractory acute myeloid leukemia or myelodysplastic neoplasia","authors":"Daniel Pollyea, Tessa Kerre, Dries Deeren, Yves Beguin, Tara L. Lin, David A. Sallman, Sebastien Anguille, William G. Blum, Anne Flament, Eytan Breman, Caroline Lonez","doi":"10.1038/s41375-025-02767-4","DOIUrl":"https://doi.org/10.1038/s41375-025-02767-4","url":null,"abstract":"<p>The NKG2D receptor binds eight ligands (NKG2DL) overexpressed in a wide range of malignancies, but largely absent on non-neoplastic cells. Initial clinical evaluation of NKG2DL chimeric antigen receptor (CAR) T-cells (CYAD-01) in patients with relapsed or refractory (r/r) acute myeloid leukemia (AML) or myelodysplastic neoplasia (MDS) demonstrated low durability of responses and short cell persistence. Two Phase I trials were initiated to evaluate the effect of lymphodepletion prior to a single CAR T-cell infusion in a similar r/r AML/MDS patient population. The DEPLETHINK trial (NCT03466320) evaluated CYAD-01 while the CYCLE-1 trial (NCT04167696) evaluated a next-generation NKG2DL CAR, CYAD-02, where the two main NKG2D ligands MICA and B are downregulated, to increase CAR T-cell persistence. Seventeen and twelve patients were treated in the DEPLETHINK and CYCLE-1 trials, and confirmed the good tolerability of both products with cytokine release syndrome (CRS) grade 3 or 4 reported in 25% and 33.3% of patients, respectively. CYAD-02 presented an higher engraftment and an improved clinical activity (17% objective response rate) compared to CYAD-01 (no objective response). Altogether, our data provide proof of principle that knock-down of MICA/B can enhance CAR T-cell persistence and efficacy while maintaining a good safety profile.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"35 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CRISPR-engineered human GATA2 deficiency model uncovers mitotic dysfunction and premature aging in HSPCs, impairing hematopoietic fitness","authors":"Damia Romero-Moya, Eric Torralba-Sales, Cristina Calvo, Oskar Marin-Bejar, Maria Magallon-Mosella, Maximiliano Distefano, Joan Pera, Julio Castaño, Francesca De Giorgio, Jessica Gonzalez, Arnau Iglesias, Clara Berenguer-Balaguer, Marcel Schilling, Mireya Plass, Lorenzo Pasquali, Albert Català, Oscar Molina, Marcin W. Wlodarski, Anna Bigas, Alessandra Giorgetti","doi":"10.1038/s41375-025-02771-8","DOIUrl":"https://doi.org/10.1038/s41375-025-02771-8","url":null,"abstract":"<p>GATA2 deficiency is a monogenic transcriptopathy disorder characterized by bone marrow failure (BMF), immunodeficiency, and a high risk of developing myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). Although informative mouse models have been developed, the mechanisms by which GATA2 haploinsufficiency drives disease initiation in humans remain incompletely understood. To address this, we developed a novel humanized model using CRISPR/Cas9 technology to knock-in GATA2-R398W variant in primary cord blood CD34⁺ cells. Additionally, we introduced specific mutations in SETBP1 and ASXL1 to model distinct premalignant stages of GATA2 deficiency. Through clonal competition and serial transplantation assays, we demonstrated that human CD34⁺ cells harboring the GATA2 mutation exhibit significantly reduced fitness in vivo when compete with wild-type cells. Notably, this fitness disadvantage persists even when GATA2 mutations are combined with oncogenic SETBP1 and ASXL1 drivers, underscoring the dominant, deleterious effect of GATA2 deficiency on hematopoietic stem cell function. Functional in vitro analyses revealed that GATA2-R398W mutation impairs cell proliferation, disrupts cell cycle progression, and induces mitotic defects, which may contribute to hematopoietic stem/progenitor cell loss and impaired self-renewal. Transcriptomic profiles of GATA2-mutant cells revealed that these functional defects are associated with reduced HSC self-renewal capacity and upregulation of the pre-aging phenotype. Our work highlights the feasibility of generating a human GATA2 deficiency model suitable for studying the biological consequences of various GATA2 variants and the generation of a platform to test potential phenotype-rescuing therapeutics.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"29 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}