Leukemia最新文献

{"title":"Targeting PI3K decreases trogocytosis-mediated CAR T cell fratricide.","authors":"Tarang Sharma, Maday Galeana Figueroa, Kishan Kumar Nyati, Ravi K Shah, Meera Mohan, Parameswaran Hari, Tim Luetkens, Sabarinath Venniyil Radhakrishnan","doi":"10.1038/s41375-026-03129-4","DOIUrl":"https://doi.org/10.1038/s41375-026-03129-4","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891975","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":"Functional characterization of snoRNA-derived RNA (sdRNA) expression in healthy hematopoiesis and acute myeloid leukemia.","authors":"Rafael Zinz, Christian Rohde, Cornelius Pauli, Fengbiao Zhou, Azmal Ali Syed, Daniel Heid, Viral Shah, Niklas Alexander Wahl, Adrija Ray, Simon Renders, Laura Werner, Sandra Förmer, Carl Ahrens, Claudia Baldus, Martin Bornhäuser, Christoph Röllig, Hubert Serve, Tim Sauer, Jeroen Krijgsveld, Carsten Müller-Tidow, Maximilian Felix Blank","doi":"10.1038/s41375-026-03120-z","DOIUrl":"https://doi.org/10.1038/s41375-026-03120-z","url":null,"abstract":"<p><p>SnoRNAs are highly expressed in AML and have implications in leukemogenesis and leukemic maintenance. SnoRNAs can be further processed into snoRNA-derived RNAs (sdRNAs). The role of sdRNAs in AML and healthy hematopoiesis remains largely elusive. We characterized sdRNA and snoRNA levels in hematopoietic stem and progenitor cells (HSPCs), healthy WBCs, and 159 intensively treated AML patient samples at initial diagnosis. HSPCs, healthy WBCs, and AML blasts could be differentiated by their sdRNA expression pattern in a cell-type-specific manner. In AML, high sd3'-RNA/snoRNA-host gene ratios were associated with an inverse patient outcome. Particularly, in NPM1-mutated patients with favorable risk stratification and good initial therapy response, high sd3'-RNA ratios identified a subgroup with inferior outcome. High sd3'-RNA ratios were associated with altered oncogenic, inflammatory, and immune response signaling. Forced expression of single sdRNAs, such as sd3'-SNORD78, sd3'-SNORD76, and sd5'-SNORD93, enhanced clonogenic potential in AML and drove sdRNA-specific gene expression signatures in both AML and healthy HSPCs. Exemplarily, we propose and characterize NUDT21, an important regulator of alternative polyadenylation and oncogenic gene expression, as a downstream target of sd3'-SNORD78 in AML. Our data introduce sdRNAs as standalone regulatory effector molecules in healthy hematopoiesis and AML.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891946","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":"Csnk1a1 E98 mutations rewire signaling and metabolism in del(5q) myelodysplastic neoplasms.","authors":"Stephani Schmitz, Juliette E Pearce, Sergio Martinez-Høyer, Gerjanne Vroeg In de Wei, Inge A M Snoeren, Ursula S A Stalmann, Stijn N R Fuchs, Aurelien J F Dugourd, Giulia Franciosa, Eric M Bindels, Wencke Walter, Claudia Meyer, Torsten Haferlach, Emiel P C van der Vorst, Oriol Calvete, Francesc Solé, Julio Saez-Rodriguez, Andreas Linkermann, Jesper Olsen, Hélène F E Gleitz, Rebekka K Schneider","doi":"10.1038/s41375-026-03122-x","DOIUrl":"https://doi.org/10.1038/s41375-026-03122-x","url":null,"abstract":"<p><p>Deletion of chromosome 5q [del(5q)] is the most common cytogenetic abnormality in myelodysplastic neoplasms (MDS) and results in haploinsufficiency of multiple genes, including CSNK1A1. Recurrent CSNK1A1 mutations, predominantly affecting the E98 hotspot, occur almost exclusively in del(5q) MDS and are associated with adverse outcomes, yet their impact on CK1ɑ function remains unclear. Using integrated transcriptomic, (phospho)proteomic, and kinome activity profiling in hematopoietic stem and progenitor cells (HSPCs), combined with in vivo serial transplantation assays, we show that Csnk1a1 E98V represents a change-of-function rather than a loss-of-function mutation. Unlike Csnk1a1 haploinsufficiency, Csnk1a1 E98V preserves long-term hematopoietic reconstitution and does not enhance clonal expansion in vivo. Instead, the mutation induces suppression of kinase signaling networks, leading to coordinated repression of ribosomal gene expression, protein translation, and cell cycle programs. This signaling rewiring is accompanied by metabolic reprogramming characterized by reduced mitochondrial respiration, increased glycolytic flux, and an inability to adapt to metabolic challenges, creating a stress-tolerant but inflexible cellular state. Notably, Csnk1a1 E98V cells exhibit impaired megakaryopoiesis and increased vulnerability to iron overload, as well as RSL-3-mediated ferroptosis. Analysis of del(5q) MDS patients confirmed that CSNK1A1 mutations are associated with distinct clinical features, including thrombocytopenia, elevated myeloblasts, and reduced bone marrow iron levels. Together, our findings support a two-step model in which del(5q)-associated CSNK1A1 haploinsufficiency drives clonal expansion, followed by acquisition of CSNK1A1 mutations that promote stress tolerance rather than increased proliferation. This adaptive rewiring exposes metabolic and iron-dependent vulnerabilities that may be therapeutically exploited.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887804","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":"Patterns of clonal hematopoiesis in aplastic anemia under immunosuppressive therapy.","authors":"Linzhu Tian, Lele Zhang, Ruonan Li, Wenyan Wang, Weiwang Li, Hong Pan, Zhen Gao, Jingyu Zhao, Yuechen Luo, Liwei Fang, Jun Shi","doi":"10.1038/s41375-026-03048-4","DOIUrl":"https://doi.org/10.1038/s41375-026-03048-4","url":null,"abstract":"<p><p>Aplastic anemia (AA) is an immune-mediated bone marrow failure disorder with 15-20% risk of clonal evolution. We analyzed 371 patients with AA receiving immunosuppressive therapy (IST). All patients underwent PNH testing and 357 evaluable for cytogenetic analysis. Two hundred and thirty-seven received serial targeted sequencing. Clonal characteristics were compared before and after IST across age, disease severity, and hematological response. Among the 237 patients, somatic mutations were detected in 53 patients (22%) at baseline and 97 (41%) after IST. Distinct patterns of mutational dynamics were observed under IST, with newly acquired mutations defined as Pattern 2 being most common. High-risk mutations such as ASXL1 expanded persistently, whereas favorable clones like BCOR and PIGA often contracted or remained stable. Older age was associated with heavier mutational burden, and disease severity was associated with greater increase in mutations. Cytogenetic abnormalities were observed in 18 of 357 patients (5%) and rose to 37 (10%) post-treatment. PNH clones were present in 20% of patients at baseline and remained relatively stable during follow-up, 15 patients progressed to PNH syndrome. Six patients evolved to myeloid neoplasms, including myelodysplastic syndromes and chronic myelomonocytic leukemia. These findings highlight the importance of long-term molecular surveillance (ClinicalTrials.gov number, NCT04645199).</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887785","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":"CD19-CAR T cells persist long-term in the cerebrospinal fluid of pediatric, adolescent and young adult patients with B-cell acute lymphoblastic leukemia.","authors":"Aimee C Talleur, Jean-Yves Métais, Ying Li, Sarah Schell, Polly Adams, Rebecca Epperly, Marleni Torres Nunez, Stephen Gottschalk, Swati Naik","doi":"10.1038/s41375-026-03108-9","DOIUrl":"https://doi.org/10.1038/s41375-026-03108-9","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887861","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":"Macrophage reprogramming, not CD8 T cell dynamics, characterizes durable disease control following PD-1 blockade in smoldering myeloma.","authors":"Noé Perron, Kane Foster, Tarek H Mouhieddine, Robert A Redd, Sophie Magidson, Jacqueline Perry, Ashlee Sturtevant, Christine Davie, Caroline Ricciardi, Frances Arters, Marjorie Marto, Amy Goguen, Yuxin Liu, Elizabeth K O'Donnell, Adam S Sperling, Jacob P Laubach, Paul G Richardson, Gad Getz, Romanos Sklavenitis-Pistofidis, Lorenzo Trippa, Yoshinobu Konishi, Omar Nadeem, Irene M Ghobrial","doi":"10.1038/s41375-026-03092-0","DOIUrl":"https://doi.org/10.1038/s41375-026-03092-0","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887878","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":"KLF4/MLL3 complex axis drives NRBP2 transcription to eliminate acute myeloid leukemia cells.","authors":"Meng Yang, Ting Lu, Yicheng He, Cong Chen, Yifei Wang, Guohuan Sun, Yawei Zheng, Jiaxin Qin, Jiali Ye, Xiaowei Xie, Xiangnan Zhao, Honglin Duan, Biao Zhang, Yapu Li, Fang Dong, Chang Xu, Tao Cheng, Hui Cheng, Shangda Yang","doi":"10.1038/s41375-026-03117-8","DOIUrl":"https://doi.org/10.1038/s41375-026-03117-8","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) is a heterogeneous malignancy rooted in hematopoietic stem cell dysregulation. Here, we identify the transcription factor Krüppel-like factor 4 (KLF4) as a potent suppressor of AML growth, with KLF4 overexpression markedly impairing AML cell proliferation. Mechanistically, KLF4 interacts with the lysine methyltransferase 2 C (MLL3/KMT2C) histone methyltransferase complex to activate transcription of nuclear receptor-binding protein 2 (NRBP2), a pseudokinase. Furthermore, integrated transcriptomic and functional analyses identify TNIK (TRAF2- and NCK-interacting kinase) as a pro-leukemic downstream effector restrained by the KLF4-NRBP2 axis. Pharmacological inhibition of TNIK with TNIK-IN-1 inhibits AML cell growth while exerting limited effects on normal hematopoietic cells. Together, these findings establish a KLF4/MLL3 complex-NRBP2 regulatory axis that restrains AML growth through suppression of TNIK expression and provide a rationale for further preclinical evaluation of TNIK inhibition as a therapeutic strategy in AML. Schematic model illustrating the mechanism by which the KLF4/MLL3 complex/NRBP2 axis regulates the progression of AML. In AML cells with basal KLF4 expression, higher expression of TNIK promotes the proliferation of AML cells (upper). Upon KLF4 overexpression, the TRD and ZnF domains of KLF4 bind to MLL3, which facilitates the recruitment of the MLL3 complex to the NRBP2 cis-regulatory regions. This activates NRBP2 transcription and subsequently downregulates TNIK expression, leading to the suppression of AML cell proliferation. Pharmacological inhibition of TNIK by TNIK-IN-1 reduces TNIK protein levels, represses AML cell growth, and induces cell apoptosis (lower). This study reveals a molecular mechanism by which KLF4 governs AML progression, providing a novel therapeutic target and a potential small-molecule inhibitor for AML treatment (Created in BioRender. he, Y. (2026) https://BioRender.com/q0q3j3q ).</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881070","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":"Jagged-dependent Notch signaling governs extracellular vesicle bioactivity in multiple myeloma.","authors":"Domenica Giannandrea, Valentina Citro, Natalia Platonova, Michela Colombo, Raffaella Adami, Lara Paonessa, Giulia Sauro, Silvia Ancona, Anna Pistocchi, Gilda Aiello, Alfonsina D'Amato, Elisabetta Calzavara, Francesca Guidotti, Gloria Sini, Mauro Turrini, Lavinia Casati, Elena Lesma, Raffaella Chiaramonte","doi":"10.1038/s41375-026-03121-y","DOIUrl":"https://doi.org/10.1038/s41375-026-03121-y","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148880995","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":"Defining and predicting disease progression in myeloproliferative neoplasms: a proposed biomarker-driven approach.","authors":"Raajit K Rampal, Richard Winneker, Andrew Kuykendall, Laura C Michaelis, Ghaith Abu-Zeinah, Steffen Koschmieder, Jan Philipp Bewersdorf, Zi Yun Ng, Gabriella Hobbs, Bridget Marcellino, Linda Resar, Joseph Scandura, Anand Patel, John Mascarenhas, Aaron Gerds, Douglas Tremblay, Shane Mayack, Andriy Derkach, Florian H Heidel","doi":"10.1038/s41375-026-03103-0","DOIUrl":"https://doi.org/10.1038/s41375-026-03103-0","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874632","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":"Choice of hypomethylating agent for newly diagnosed TP53-mutant acute myeloid Leukemia: a COMMAND registry study.","authors":"Talha Badar, James Foran, Omer Jamy, Chenyu Lin, Anand Patel, Yu-Hung Wang, Mahesh Kumar, Rory M Shallis, Kendall Diebold, Alexander Coltoff, Aaron D Goldberg, Jan P Bewersdorf, Kenneth M Zabel, Charles Foucar, Yasmin Abaza, Guru S Murthy, Neil Palmisiano, Adam S DuVall, Vamsi Kota, Shyam A Patel, Amer M Zeidan, Hemant Murthy, Mohamed Kharfan-Dabaja, Ehab Atallah, Mark R Litzow","doi":"10.1038/s41375-026-03119-6","DOIUrl":"https://doi.org/10.1038/s41375-026-03119-6","url":null,"abstract":"<p><p>Although azacitidine (AZA) and decitabine (DEC) demonstrate comparable efficacy in AML, prior data suggest that DEC may induce deeper TP53 mutation clearance and higher response rates; however, direct comparisons in TP53-mutant (TP53-MT) AML are lacking. We conducted a large multicenter retrospective analysis to compare outcomes between DEC- and AZA-based induction, including combinations with venetoclax (VEN). Of 652 patients with newly diagnosed TP53-MT AML, 321 received HMA-based induction (DEC, n = 183; AZA, n = 138). Baseline clinical and genomic characteristics were comparable between the DEC and AZA groups. TP53 mutation subtype were not associated with outcomes, whereas multi-hit TP53 status was independently associated with inferior EFS and OS. In the propensity score-matched cohort, no significant differences in event-free survival (EFS; P = 0.920) or overall survival (OS; P = 0.927) were observed. Median EFS was 5.1, 3.4, 5.9, and 5.6 months, with 12-month estimates of 24%, 17%, 18%, and 16%, while median OS was 5.7, 7.1, 9.2, and 7.1 months, with corresponding 12-month OS rates of 31%, 23%, 29%, and 32% for DEC + VEN, AZA + VEN, DEC, and AZA, respectively. No significant pairwise differences were observed between regimens. These findings from a large multicenter cohort suggest that AZA- and DEC-based induction yield comparable survival outcomes in TP53-MT AML.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148865553","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}