LeukemiaPub Date : 2025-09-10DOI: 10.1038/s41375-025-02748-7
Denis Ohlstrom, Mojtaba Bakhtia, 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
{"title":"Longitudinal single-cell analysis reveals treatment-resistant stem and mast cells with potential treatments for pediatric AML","authors":"Denis Ohlstrom, Mojtaba Bakhtia, 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/s41375-025-02748-7","DOIUrl":"https://doi.org/10.1038/s41375-025-02748-7","url":null,"abstract":"<p>Pediatric acute myeloid leukemia (pAML) is a heterogeneous malignancy driven by diverse cytogenetic mutations. While identification of cytogenetic lesions improved risk stratification, prognostication remains inadequate with 30% of standard-risk patients experiencing relapse within 5 years. To deeply characterize pAML heterogeneity and identify poor outcome-associated blast cell profiles, we performed an analysis on 708,285 cells from 164 bone marrow biopsies of 95 patients and 11 healthy controls. The longitudinal analysis on cell abundances at the time of disease diagnosis, end of induction, and relapse identified treatment resistant stem-like blast cells specific to RUNX1::RUNX1T1, FLT3-ITD, and CBFB::MYH11 patients that are associated with poor outcomes. Treatment resistant blast cells from RUNX1::RUNX1T1 were found to associate with T cell exhaustion, while those from FLT-ITD utilized enriched antioxidant metabolism to persist through treatment. Interestingly, the analysis also identified novel mast cell-like pAML associated with treatment resistance and poor outcomes. Deconvolution of ex vivo treatment data and subsequent in vitro validation identified bortezomib (RUNX1), ponatinib, and venetoclax (FLT3) as specifically potent against treatment resistant blasts from the respective cytogenetic groups. Our findings indicate immature and mature pAML subtypes are promising biomarkers for enhanced patient risk stratification and identifies targeted agents to increase their clearance after treatment.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"71 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025310","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}
LeukemiaPub Date : 2025-09-09DOI: 10.1038/s41375-025-02750-z
Roshina Thapa, Kim E. Nichols, Richa Sharma
{"title":"Insights into germline predisposition to pediatric lymphoid malignancies","authors":"Roshina Thapa, Kim E. Nichols, Richa Sharma","doi":"10.1038/s41375-025-02750-z","DOIUrl":"https://doi.org/10.1038/s41375-025-02750-z","url":null,"abstract":"<p>Hematopoietic malignancies (HM) represent the most common form of pediatric cancer with lymphoid malignancies being the predominant subtype in kids. The majority of lymphoid malignancies are proposed to occur sporadically with environmental, infectious and inflammatory triggers impacting oncogenesis in ways that are not yet fully understood. With the increased adoption of germline genetic testing in children with cancer, genetic predisposition to lymphoid malignancies is now recognized as an important aspect of clinical care and research. Pathogenic variants in genes important for lymphocyte development, including cell differentiation, DNA recombination, recognition and repair of DNA damage, apoptosis, RNA processing, and intracellular signaling all converge on an increased risk for lymphoid malignancies. Herein, we review several genetic predispositions to lymphoid malignancies with a focus on the underlying biological defect, as well as the associated oncologic and non-oncologic manifestations.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"16 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025308","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}
LeukemiaPub Date : 2025-09-05DOI: 10.1038/s41375-025-02730-3
Adriano Venditti, Jing-Zhou Hou, Pierre Fenaux, Brian A. Jonas, Radovan Vrhovac, Pau Montesinos, Jacqueline S. Garcia, David Rizzieri, Michael J. Thirman, Meng Zhang, Jalaja Potluri, Catherine Miller, Mazaher Dhalla, Vinod Pullarkat
{"title":"Outcomes of patients treated with venetoclax plus azacitidine versus azacitidine alone stratified by advanced age and acute myeloid leukemia composite model","authors":"Adriano Venditti, Jing-Zhou Hou, Pierre Fenaux, Brian A. Jonas, Radovan Vrhovac, Pau Montesinos, Jacqueline S. Garcia, David Rizzieri, Michael J. Thirman, Meng Zhang, Jalaja Potluri, Catherine Miller, Mazaher Dhalla, Vinod Pullarkat","doi":"10.1038/s41375-025-02730-3","DOIUrl":"https://doi.org/10.1038/s41375-025-02730-3","url":null,"abstract":"<p>Venetoclax plus azacitidine is recognized as standard of care for patients with acute myeloid leukemia (AML) ineligible for intensive chemotherapy (IC). However, some patients may still not be treated with venetoclax combinations due to frailty concerns. We evaluated efficacy and safety of venetoclax plus azacitidine vs. placebo plus azacitidine in patients with newly diagnosed AML ineligible for IC from the phase 3 VIALE-A study (NCT02993523) and the phase 1b M14-358 study (NCT02203773), stratified by two methods to potentially assess frailty. The first method was age-based (75–79, 80–84, ≥85 years; <i>n </i>= 303 pooled from both studies) and the second was fitness-based using the AML composite model (AML-CM), a comorbidity-based model to estimate mortality risk (Group A, B, C; <i>n </i>= 380, from VIALE-A). Efficacy, including composite complete remission and overall survival, were improved with venetoclax plus azacitidine vs. placebo plus azacitidine across age and AML-CM groups. Safety was generally similar between age and AML-CM groups and no new safety signals were identified. Taken together, these data suggest that patients benefit from venetoclax plus azacitidine regardless of age or degree of frailty and the combination may be considered for patients with AML who may be deemed frail. Clinical trial information NCT02993523; NCT02203773.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"65 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995493","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}
LeukemiaPub Date : 2025-09-05DOI: 10.1038/s41375-025-02760-x
Alexandre Bazinet, Guillermo Montalban-Bravo, Alex Bataller, Danielle Hammond, Sanam Loghavi, Kelly Chien, Koji Sasaki, Ian Bouligny, Mahesh Swaminathan, Wei Ying Jen, Uday Popat, Tapan Kadia, Courtney DiNardo, Elias Jabbour, Nicholas Short, Naval Daver, Farhad Ravandi, Guillermo Garcia-Manero
{"title":"Impact of discordant revised versus molecular international prognostic scoring system risk in myelodysplastic syndrome","authors":"Alexandre Bazinet, Guillermo Montalban-Bravo, Alex Bataller, Danielle Hammond, Sanam Loghavi, Kelly Chien, Koji Sasaki, Ian Bouligny, Mahesh Swaminathan, Wei Ying Jen, Uday Popat, Tapan Kadia, Courtney DiNardo, Elias Jabbour, Nicholas Short, Naval Daver, Farhad Ravandi, Guillermo Garcia-Manero","doi":"10.1038/s41375-025-02760-x","DOIUrl":"https://doi.org/10.1038/s41375-025-02760-x","url":null,"abstract":"<p><b>TO THE EDITOR</b>:</p><p>Myelodysplastic syndromes (MDS) are hematopoietic stem cell (HSC) neoplasms that arise through a stepwise evolutionary process due to the expansion of clonal HSCs [1, 2]. The Revised International Prognostic Scoring System (IPSS-R), based on clinical and pathologic characteristics, has long been the standard risk stratification system used in clinical trials and practice [3]. Recent efforts have integrated genomic data within the Molecular International Prognostic Scoring System (IPSS-M) [4]. Compared to the IPSS-R, the IPSS-M results in a change in risk category in a significant number of patients, with major clinical implications. Indeed, the classification of a patient as either higher risk (HR) or lower risk (LR) is fundamental in the management of MDS, with widely differing treatment approaches. In this study, we evaluated a large cohort of patients with MDS and compared the characteristics and clinical behavior of patients who experienced a change in overall risk (HR versus LR) when re-stratified from IPSS-R to IPSS-M.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"34 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995492","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}
LeukemiaPub Date : 2025-09-03DOI: 10.1038/s41375-025-02747-8
Tim R. Mocking, Lukas H. Haaksma, Tom Reuvekamp, Angèle Kelder, Willemijn J. Scholten, Lok Lam Ngai, Dimitri A. Breems, Thomas Fischer, Bjørn T. Gjertsen, Laimonas Griškevičius, Gunnar Juliusson, Johan A. Maertens, Markus G. Manz, Thomas Pabst, Jakob R. Passweg, Kimmo Porkka, Peter J. M. Valk, Patrycja Gradowska, Bob Löwenberg, David C. de Leeuw, Jeroen J. W. M. Janssen, Gert J. Ossenkoppele, Arjan A. van de Loosdrecht, Jacqueline Cloos, Costa Bachas
{"title":"Computational measurable residual disease assessment in acute myeloid leukemia: a retrospective validation in the HOVON-SAKK-132 trial","authors":"Tim R. Mocking, Lukas H. Haaksma, Tom Reuvekamp, Angèle Kelder, Willemijn J. Scholten, Lok Lam Ngai, Dimitri A. Breems, Thomas Fischer, Bjørn T. Gjertsen, Laimonas Griškevičius, Gunnar Juliusson, Johan A. Maertens, Markus G. Manz, Thomas Pabst, Jakob R. Passweg, Kimmo Porkka, Peter J. M. Valk, Patrycja Gradowska, Bob Löwenberg, David C. de Leeuw, Jeroen J. W. M. Janssen, Gert J. Ossenkoppele, Arjan A. van de Loosdrecht, Jacqueline Cloos, Costa Bachas","doi":"10.1038/s41375-025-02747-8","DOIUrl":"10.1038/s41375-025-02747-8","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 10","pages":"2559-2562"},"PeriodicalIF":13.4,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02747-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144960245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Targeting HDAC8 sensitizes tyrosine kinase inhibitors in the elimination of B-cell acute lymphoblastic leukemia cells through degradation of HIF-1α","authors":"Guilin Xu, Feng Wang, Ming Chen, Wenhui Gao, Ying Liu, Jiayan Zhu, Churan Wang, Huimin Jiang, Yunxuan Li, Peitao Zhang, Jian Yuan, Tingting Zhang, Chenxi Zhao, Lining Wang, Ling Wang, Jieling Jiang, Wenbin Cao, Zhuan Zhang, Haigen Fu, Ting Dong, Jiong Hu, Ke Li","doi":"10.1038/s41375-025-02749-6","DOIUrl":"https://doi.org/10.1038/s41375-025-02749-6","url":null,"abstract":"<p>Tyrosine kinase inhibitors (TKIs) only partially inhibit the growth of Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph<sup>+</sup> B-ALL) cells, and often lead to rapid relapse. Therefore, it is essential to elucidate the mechanisms of resistance and develop novel treatment strategies. Histone deacetylases (HDACs) are often dysregulated in hematological malignancies, and many HDAC inhibitors have shown potent antitumor activities. In this study, we found that HDAC8 was highly expressed in Ph<sup>+</sup> B-ALL patient samples upon TKI treatment. HDAC8 inhibition significantly increased TKI-mediated elimination of leukemia cells and decreased their ability to initiate leukemia. Using two mouse models, we demonstrated that TKIs in combination with targeting HDAC8 effectively inhibited leukemia progression and reduced the frequencies of stem cells. Mechanistically, HDAC8 deacetylated hypoxia inducible factor-1α (HIF-1α) at lysine 19/21, leading to a reduction in PHD2-mediated hydroxylation and subsequent pVHL-mediated ubiquitination, which slowed the degradation of HIF-1α. HIF-1α inhibition induced apoptosis and decreased the initiating capacity of leukemia cells. Importantly, in a Ph<sup>+</sup> B-ALL patient–derived xenograft model, targeting HDAC8 or HIF-1α in combination with TKIs significantly inhibited leukemia progression. In conclusion, our study revealed that targeting HDAC8/HIF-1α in combination with TKIs could be a promising strategy for treating Ph<sup>+</sup> B-ALL.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"1 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928248","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}
LeukemiaPub Date : 2025-09-01DOI: 10.1038/s41375-025-02744-x
Ana Alfonso-Pierola, David Martinez-Cuadrón, Rebeca Rodríguez-Veiga, Cristina Gil, Pilar Martínez-Sánchez, Teresa Bernal, Celina Benavente, Mónica A. Romero-Riquelme, Josefina Serrano-Lopez, Juan M. Bergua, Raimundo García-Boyero, Mar Tormo, Pilar Herrera, Claudia L. Sossa-Melo, José A. Pérez-Simon, Carlos Rodríguez-Medina, María F. Bass-Maturana, José L. López-Lorenzo, Lorenzo Algarra-Algarra, Belén Vidriales-Vicente, Manuel Pérez-Encinas, Manuel Barrios-García, Susana Vives, María J. Sayas-Lloris, Marisa Capurro, Sebastián Hidalgo, Mayte Olave, Diana Cuervo-Lozada, Esperanza Lavilla-Rubira, Felipe Casado, Armando Mena-Durán, Marta Valero-Nuñez, Soledad Casado-Calderón, Amaia Balerdi, Vivianne Torres, Rosa Fernández, Víctor Noriega, Mariana Stevenazzi, Jorge Labrador, Pilar León-Maldonado, Beatriz de Rueda-Ciller, Olga Arce-Fernández, María L. Amigo, José Ángel Raposo-Puglia, María Solé, Blanca Boluda, Rosa Ayala, Eva Barragán, Pau Montesinos
{"title":"Long-term benefits of autologous stem cell transplantation versus intensive chemotherapy consolidation for acute myeloid leukemia patients: A propensity score matching analysis from the PETHEMA AML registry","authors":"Ana Alfonso-Pierola, David Martinez-Cuadrón, Rebeca Rodríguez-Veiga, Cristina Gil, Pilar Martínez-Sánchez, Teresa Bernal, Celina Benavente, Mónica A. Romero-Riquelme, Josefina Serrano-Lopez, Juan M. Bergua, Raimundo García-Boyero, Mar Tormo, Pilar Herrera, Claudia L. Sossa-Melo, José A. Pérez-Simon, Carlos Rodríguez-Medina, María F. Bass-Maturana, José L. López-Lorenzo, Lorenzo Algarra-Algarra, Belén Vidriales-Vicente, Manuel Pérez-Encinas, Manuel Barrios-García, Susana Vives, María J. Sayas-Lloris, Marisa Capurro, Sebastián Hidalgo, Mayte Olave, Diana Cuervo-Lozada, Esperanza Lavilla-Rubira, Felipe Casado, Armando Mena-Durán, Marta Valero-Nuñez, Soledad Casado-Calderón, Amaia Balerdi, Vivianne Torres, Rosa Fernández, Víctor Noriega, Mariana Stevenazzi, Jorge Labrador, Pilar León-Maldonado, Beatriz de Rueda-Ciller, Olga Arce-Fernández, María L. Amigo, José Ángel Raposo-Puglia, María Solé, Blanca Boluda, Rosa Ayala, Eva Barragán, Pau Montesinos","doi":"10.1038/s41375-025-02744-x","DOIUrl":"https://doi.org/10.1038/s41375-025-02744-x","url":null,"abstract":"<p>While allogeneic stem cell transplantation (allo-SCT) is the preferred consolidation for high and most intermediate-risk acute myeloid leukemia (AML) patients in first remission, the role of autologous SCT (auto-SCT) vs. chemotherapy (CT) when allo-SCT is not feasible or indicated, remains controversial. We conducted a real-world, retrospective cohort study using the PETHEMA AML registry to compare auto-SCT and CT. Multivariate Cox regression and propensity score matching (PS-matching) were used to adjust for confounding factors. A total of 1272 patients in first remission and who received 2 consolidation courses were included (615 receiving additional CT cycles and 657 undergoing auto-SCT). Overall, 78.08% of auto-SCT patients were diagnosed before 2017, compared to 38.11% in the CT cohort (<i>p</i> < 0.001). In the overall cohort, auto-SCT was associated with significantly prolonged overall survival (OS) (HR: 0.73, <i>p</i> < 0.001) and relapse-free survival (RFS) (HR: 0.73, <i>p</i> < 0.001). This benefit was particularly evident in patients ≤65 years, those with normal karyotype, and FLT3-ITD negativity. In the PS-matched cohort, the RFS advantage persisted (HR: 0.80, <i>p</i> = 0.092), but OS differences were not statistically significant (HR: 0.91, <i>p</i> = 0.563). The role of auto-SCT in the genomic and targeted agent era should not be discarded.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"60 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144923939","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}
LeukemiaPub Date : 2025-08-26DOI: 10.1038/s41375-025-02732-1
Nikola Curik, Adam Laznicka, Jitka Krizkova, Pavla Suchankova, Adela Vavrova, Vaclava Polivkova, Eva Pokorna, Pavel Semerak, Pavel Burda, Daniela Kuzilkova, Tomas Kalina, Andreas Hochhaus, Katerina Machova Polakova
{"title":"Venetoclax in combination with ponatinib for the treatment of asciminib-resistant chronic myeloid leukemia","authors":"Nikola Curik, Adam Laznicka, Jitka Krizkova, Pavla Suchankova, Adela Vavrova, Vaclava Polivkova, Eva Pokorna, Pavel Semerak, Pavel Burda, Daniela Kuzilkova, Tomas Kalina, Andreas Hochhaus, Katerina Machova Polakova","doi":"10.1038/s41375-025-02732-1","DOIUrl":"10.1038/s41375-025-02732-1","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 10","pages":"2555-2558"},"PeriodicalIF":13.4,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02732-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
LeukemiaPub Date : 2025-08-26DOI: 10.1038/s41375-025-02740-1
Jonas Thier, Sophia Hofmann, Katharina M. Kirchhof, Gabriele Todisco, Teresa Mortera-Blanco, Ingrid Lilienthal, Dimitris C. Kanellis, Indira Barbosa, Ann-Charlotte Björklund, André G. Deslauriers, Jiri Bartek, Nikolas Herold, Elli Papaemmanuil, Eirini P. Papapetrou, Eva Hellström-Lindberg, Pedro L. Moura, Vanessa Lundin
{"title":"SF3B1-mutant models of RNA mis-splicing uncover UBA1 as a therapeutic target in myelodysplastic neoplasms","authors":"Jonas Thier, Sophia Hofmann, Katharina M. Kirchhof, Gabriele Todisco, Teresa Mortera-Blanco, Ingrid Lilienthal, Dimitris C. Kanellis, Indira Barbosa, Ann-Charlotte Björklund, André G. Deslauriers, Jiri Bartek, Nikolas Herold, Elli Papaemmanuil, Eirini P. Papapetrou, Eva Hellström-Lindberg, Pedro L. Moura, Vanessa Lundin","doi":"10.1038/s41375-025-02740-1","DOIUrl":"https://doi.org/10.1038/s41375-025-02740-1","url":null,"abstract":"<p>Myelodysplastic syndromes with somatic mutations in the splicing factor <i>SF3B1</i> gene (MDS-<i>SF3B1</i>) result in RNA mis-splicing, erythroid dysplasia and ultimately refractory anemia. Precision medicine approaches for MDS-<i>SF3B1</i> remain challenging due to both the complexity of the mis-splicing landscape and its evaluation in disease-accurate models. To uncover novel RNA mis-splicing events, isogenic <i>SF3B1</i><sup>K700E</sup> and <i>SF3B1</i><sup>WT</sup> iPSC lines from an MDS-<i>SF3B1</i> patient were differentiated into hematopoietic cells and analyzed via unsupervised splicing event profiling using full-length RNA sequencing. This identified <i>SF3B1</i><sup>K700E</sup>-specific mis-splicing of ubiquitin-like modifier activating enzyme 1 (<i>UBA1</i>), which encodes a key E1 protein at the apex of the ubiquitination cascade. <i>UBA1</i> mis-splicing (<i>UBA1</i><sup>ms</sup>) introduced protein instability and decreased total UBA1 levels, rendering mutated cells susceptible to the small-molecule UBA1 inhibitor TAK-243. Analysis of CD34<sup>+</sup> RNA sequencing data from an MDS patient cohort confirmed unique and ubiquitous <i>UBA1</i><sup>ms</sup> in MDS-<i>SF3B1</i> patients, absent in other splicing factor-mutated MDS cases or healthy controls. TAK-243 selectively targeted MDS-<i>SF3B1</i> primary CD34<sup>+</sup> cells and reduced mutant cell numbers in colony-forming assays. In contrast, normal hematopoietic progenitor cells were unaffected. Altogether, we here define <i>UBA1</i><sup>ms</sup> as a novel therapeutic vulnerability in <i>SF3B1</i>-mutant cells, introducing UBA1 inhibition as a potential avenue for future MDS-<i>SF3B1</i> treatments.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"24 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899260","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}