Leukemia最新文献

{"title":"CAR T-cells targeting CD117 effectively eliminate mast cells in preclinical models of advanced systemic mastocytosis.","authors":"Anne Kaiser, Veronika Lysenko, Renier Myburgh, Laura Volta, Christian Pellegrino, Alexandre P A Theocharides, Deborah Christen, Jens Panse, Marco M Bühler, Michel Arock, Joseph Butterfield, Marcelo A S de Toledo, Peter Valent, Martin Zenke, Tim H Brümmendorf, Markus G Manz","doi":"10.1038/s41375-026-02968-5","DOIUrl":"https://doi.org/10.1038/s41375-026-02968-5","url":null,"abstract":"<p><p>Systemic mastocytosis (SM) is characterized by uncontrolled expansion of neoplastic mast cells (MCs) and their accumulation in various tissues and organs, ranging from indolent variants to more advanced forms (advSM). Although several MC- and SM-expressed cell surface antigens have been identified, no immune therapy has been developed for advSM so far. The receptor tyrosine kinase KIT (CD117) is highly expressed on MCs, exceeding the levels of expression on hematopoietic stem and progenitor cells (HSPC). Therefore, targeting CD117 in advSM could be of therapeutic value. In this study, we assessed the therapeutic potential of anti-CD117 chimeric antigen receptor (CAR) T-cells to target neoplastic MCs in SM. In vitro, anti-CD117-CAR T-cells efficiently lysed several SM-related human MC cell lines, MCs differentiated from SM patient-derived induced pluripotent stem (iPS) cells, and neoplastic bone marrow cells obtained from SM patients. Furthermore, in immunocompromised mice engrafted with an advSM-like MC cell line, repetitive applications of anti-CD117-CAR T-cells were able to inhibit MC expansion. These data may pave the way for the development of anti-CD117-CAR T-cell therapies in advSM.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839482","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":"U2af1^S34F and U2af1^Q157R myeloid neoplasm-associated hotspot mutations induce distinct hematopoietic phenotypes in mice.","authors":"Michael O Alberti, Sridhar Nonavinkere Srivatsan, Jin Shao, Dennis L Fei, Mengou Zhu, Claudia Cabrera Pastrana, Monique Chavez, Stefan P Tarnawsky, Sarah Grieb, Timothy A Graubert, Omar Abdel-Wahab, Matthew J Walter","doi":"10.1038/s41375-026-02974-7","DOIUrl":"https://doi.org/10.1038/s41375-026-02974-7","url":null,"abstract":"<p><p>Recurrent somatic mutations in the spliceosome genes SF3B1, SRSF2, and U2AF1 are frequently identified in patients with myeloid neoplasms, such as myelodysplastic syndromes. We characterized the in vivo consequences of expressing two hotspot mutations in U2AF1 that code for the S34F and Q157R substitutions. Our results indicate that the two mutations induce distinct hematopoietic phenotypes in mice, suggesting that the U2AF1^S34F and U2AF1^Q157R mutations should not be conflated as they may impact disease pathogenesis differently in patients. Mice expressing U2af1^S34F have a more severe reduction in their blood and bone marrow cell counts and reduced stem cell repopulating ability, compared to mice expressing U2af1^Q157R. The expression and splicing of target genes are largely unique between the mutations, in both mouse and human samples, potentially driving the phenotypic differences induced by either mutation. The two mutations co-occur with different gene mutations in patients and are not equally represented across myeloid neoplasms, suggesting that multiple mechanisms likely drive U2AF1-mutant disease pathogenesis. Collectively, our results support that U2AF1^S34F and U2AF1^Q157R mutations induce distinct hematopoietic, gene expression, and RNA splicing phenotypes in vivo. Larger population studies will be needed to determine if these phenotypic changes translate into clinico-pathologic differences in patients, warranting separate classification.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839686","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":"Editorial Expression of Concern: Discovery of a BTK/MNK dual inhibitor for lymphoma and leukemia.","authors":"H Wu, C Hu, A Wang, E L Weisberg, Y Chen, C-H Yun, W Wang, Y Liu, X Liu, B Tian, J Wang, Z Zhao, Y Liang, B Li, L Wang, B Wang, C Chen, S J Buhrlage, Z Qi, F Zou, A Nonami, Y Li, S M Fernandes, S Adamia, R M Stone, I A Galinsky, X Wang, G Yang, J D Griffin, J R Brown, M J Eck, J Liu, N S Gray, Q Liu","doi":"10.1038/s41375-026-02980-9","DOIUrl":"https://doi.org/10.1038/s41375-026-02980-9","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839532","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":"Clinical and molecular characterization of thrombocytosis in transient abnormal myelopoiesis.","authors":"Satoshi Saida, Tsutomu Toki, Ritsuko Shimizu, Asahito Hama, Takao Deguchi, Genki Yamato, Rika Kanezaki, Shotaro Iwamoto, Mari Morimoto, Daisuke Hasegawa, Takahiro Ueda, Tomoko Yokosuka, Kyogo Suzuki, Akira Shimada, Yasuhide Hayashi, Etsuro Ito, Kenichiro Watanabe, Kiminori Terui, Hideki Muramatsu","doi":"10.1038/s41375-026-02960-z","DOIUrl":"https://doi.org/10.1038/s41375-026-02960-z","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839454","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":"A novel CRLF2-targeted antibody-drug conjugate exhibits potent anti-leukemic activity against Ph-like acute lymphoblastic leukemia.","authors":"Sara M A Mohamed, Peter Schofield, Kathryn Evans, Karl-Heinz Friedrich, Daniel Christ, Narges Bayat, Richard B Lock","doi":"10.1038/s41375-026-02976-5","DOIUrl":"https://doi.org/10.1038/s41375-026-02976-5","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839509","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":"MDM2 inhibitors in myeloid cancers: from basic biology to clinical use in myeloproliferative neoplasms.","authors":"Haifa K Al-Ali, Sarah T Heidel, Francesca Palandri, Florian H Heidel","doi":"10.1038/s41375-026-02975-6","DOIUrl":"https://doi.org/10.1038/s41375-026-02975-6","url":null,"abstract":"<p><p>Pharmacologic targeting of murine double minute 2 (MDM2) represents one of the most compelling strategies for therapeutic reactivation of wild-type p53 in hematologic malignancies. The MDM2-p53 autoregulatory loop is a central regulator of cellular stress responses, and in myeloid neoplasms-including acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN)-p53 is frequently retained but functionally suppressed through MDM2 overexpression and oncogenic signaling, notably via JAK-STAT activation. Over the past decade, successive generations of MDM2 inhibitors have translated structural and mechanistic insights into clinical investigation, yielding critical lessons regarding dosing paradigms, hematologic toxicity, biomarker-driven patient selection, and mechanisms of resistance, including TP53-mutant clonal selection. While early phase III trials in AML were negative, recent studies in myelofibrosis demonstrate clinically meaningful spleen, symptom, and molecular responses, supporting disease-modifying potential in TP53-wild-type settings. Adaptive platform designs and rational combinations with JAK inhibitors, BCL-2 antagonists, and interferons have further refined therapeutic strategies. Emerging MDM2 degraders and next-generation agents aim to overcome feedback limitations and improve therapeutic index. This review integrates mechanistic foundations, clinical development, resistance biology, and future directions, highlighting how decades of basic science have reshaped p53 reactivation into a precision therapeutic paradigm in myeloid disease.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839460","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":"MECOM promotes leukemia progression and inhibits mast cell differentiation through functional competition with GATA2.","authors":"Kohei Iida, Mayuko Nakanishi, Jakushin Nakahara, Shuhei Asada, Tomoya Isobe, Tomohiro Yabushita, Tsuyoshi Fukushima, Yosuke Tanaka, Manabu Ozawa, Yasuhiro Yamada, Toshio Kitamura, Keita Yamamoto, Susumu Goyama","doi":"10.1038/s41375-026-02977-4","DOIUrl":"https://doi.org/10.1038/s41375-026-02977-4","url":null,"abstract":"<p><p>MECOM is a transcription factor critical for the maintenance of hematopoietic stem cells (HSCs) and the pathogenesis of myeloid leukemia. Germline mutations clustered in the C-terminal zinc finger domain (ZFD) of MECOM are known to cause MECOM-associated syndromes, involving bone marrow failure and skeletal anomalies. However, the molecular consequences of these mutations and the precise downstream mechanisms of MECOM remain elusive. Here, we demonstrate that the C-terminal ZFD serves as the dominant DNA-binding module of MECOM, and that disease-associated mutations abrogate its DNA-binding capacity. Mechanistically, we reveal that MECOM functionally antagonizes GATA2 via C-terminal ZFD-mediated DNA binding and recruitment of the corepressor CtBP. This repression promotes myeloid leukemogenesis while suppressing mast cell differentiation. Furthermore, we generated a knockin mouse model harboring a C-terminal ZFD mutation, which successfully recapitulated the clinical phenotypes of MECOM-associated syndromes, including reduction of HSCs and B cells. Collectively, our findings define C-terminal ZFD mutations as loss-of-function mutations with impaired DNA binding, uncover the MECOM-GATA2 axis as a key regulatory pathway, and provide a valuable mouse model for understanding MECOM-associated syndromes.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839493","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":"Smoldering multiple myeloma in transition: redefining early myeloma in the modern era.","authors":"Ola Landgren","doi":"10.1038/s41375-026-02979-2","DOIUrl":"https://doi.org/10.1038/s41375-026-02979-2","url":null,"abstract":"<p><p>Smoldering multiple myeloma (SMM) has long been viewed as an intermediate precursor state, monitored until symptoms or organ dysfunction signaled the transition to active multiple myeloma (MM). Over the past decade, however, major advances in molecular biology, modern imaging, and immunotherapy have reshaped our understanding of early plasma cell disorders. The recent FDA approval of daratumumab for high-risk SMM marks a historic turning point. For the first time, early intervention is not only feasible but clinically validated. This evolving framework challenges long-standing assumptions regarding diagnostic boundaries, risk stratification, and the traditional \"watch-and-wait\" paradigm. It is logical to conjecture that emerging and future technologies will redefine portions of today's SMM population as early myeloma, while others may ultimately be reclassified as benign monoclonal gammopathies. An interesting question is whether there will be any SMM patients left? This article reviews how the field has arrived at this new therapeutic era, outlines its limitations, and highlights key scientific and clinical questions that will shape the next generation of SMM research and care.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839666","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":"How should myelodysplastic neoplasms with isolated deletion 5q and TP53 multihit alterations be classified?","authors":"Maria Julia Montoro, Pamela Acha, Claudia Haferlach, Onyee Chan, Víctor Navarro, Yasuo Kubota, Felicitas Schulz, Robert Briski, Najla H Al Ali, Blanca Xicoy, Laura Palomo, Felix López-Cadenas, Francesc Bosch, Manja Meggendorfer, Teresa González, Lea Naomi Eder, Andrés Jerez, YuHung Wang, Alessia Campagna, Beate Betz, Valeria Santini, Teresa Bernal, Esperanza Such, Anne Sophie Platzbecker, Tariq Kewan, Carmelo Gurnari, Carla Zindel, Austin Kulasekararaj, Maria Teresa Voso, Mikkael Sekeres, Nicolas Díaz-Varela, Aref Al-Kali, Antonella Polini, Elisa Diral, Mara Memoli, Uwe Platzbecker, Detlef Haase, Amer M Zeidan, María Díez-Campelo, Guillermo Garcia-Manero, Daniel H Wiseman, Matteo G Della Porta, Ulrich Germing, Jaroslaw Maciejewski, Rami S Komrokji, Francesc Solé, Torsten Haferlach, Pierre Fenaux, David Valcárcel","doi":"10.1038/s41375-026-02939-w","DOIUrl":"https://doi.org/10.1038/s41375-026-02939-w","url":null,"abstract":"<p><p>Myelodysplastic neoplasms (MDS) with TP53 multihit alterations are associated with dismal outcomes. MDS with isolated del(5q) present favorable prognosis but is defined by the absence of TP53 multihit alterations. However, whether TP53 multihit alterations exert the same adverse impact in this genetic context remains uncertain. We retrospectively analyzed the characteristics and outcome of 43 patients with MDS with isolated del(5q) harboring TP53 multihit alterations (MDS-del(5q) TP53 multihit) and compared with 68 patients with low-blast MDS with TP53 multihit and without isolated del(5q) (MDS-LB TP53 multihit). Patients with MDS-del(5q) TP53 multihit showed significantly higher platelet counts, more frequent SF3B1 mutations, were less often classified as high-risk by IPSS-R or IPSS-M, and had significantly better outcomes than patients with MDS-LB TP53 multihit: overall survival of 70.2 vs 13.9 months, and time to acute myeloid leukemia progression (AML) of 31.9 vs 7.2 months, respectively. Moreover, the superior outcomes of MDS-del(5q) TP53 multihit patients persisted significant even when compared with MDS-LB TP53 multihit cases without complex karyotype (survival of 70.2 vs 39.9 months; time to AML progression of 31.9 vs 11.4 months). These findings indicate that, in MDS-del(5q) the adverse impact of TP53 multihit alterations may be less important than in other MDS subtypes.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816609","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":"Reduced-intensity reinduction for children and young persons with relapsed acute lymphoblastic leukemia.","authors":"Angus Hodder, Avijeet Mishra, Amir Enshaei, Susan Baird, Kaljit Bhuller, Anna Castleton, Katherine Clesham, Philip Connor, Ismail Elbeshlawi, Michael Gattens, Lindsay George, Nicholas Heaney, Danielle Ingham, Galina Jigoulina, Katherine Lindsay, Majid Madni, Andrea Malone, Bethany Mitchell, Jayashree Motwani, Emma Nicholson, Katharine Patrick, Subramaniam Ramanathan, Gordon Taylor, Sanjay Tewari, Indu Thakur, Lamia Samrin, Vanessa McLelland, Caroline Osborne, Laura E Hogan, Stacy Cooper, Lingyun Ji, Deepa Bhojwani, Patrick A Brown, Stephen P Hunger, Mignon L Loh, Denise Bonney, Michelle Cummins, Frederik van Delft, Sara Ghorashian, Christina Halsey, Rachael Hough, Anthony Moorman, John Moppett, Sujith Samarasinghe, Ajay Vora, David O'Connor","doi":"10.1038/s41375-026-02923-4","DOIUrl":"https://doi.org/10.1038/s41375-026-02923-4","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775462","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}