Leukemia最新文献

{"title":"Models for T-large granular lymphocytic leukemia: how to mimic the cellular interplays in malignant autoimmunity","authors":"Hanna Klepzig, Marco Herling, Natali Pflug, Till Braun","doi":"10.1038/s41375-025-02553-2","DOIUrl":"10.1038/s41375-025-02553-2","url":null,"abstract":"T-large granular lymphocytic leukemia (T-LGLL) is a chronic lymphoproliferative disorder characterized by clonal expansions of cytotoxic T-cells. It presents with cytopenias that are not explained by the typically low leukemic burden. Notably, T-LGLL is frequently accompanied by autoimmune disorders, particularly rheumatoid arthritis (RA). As clonal T-cell expansions are also increasingly identified in autoimmune-driven conditions, better models of T-LGLL’s pathogenesis as a spectrum of (auto)antigen-driven oligoclonal hierarchies towards overt leukemic escape with associated immune dysregulations would provide details to a valuable prototype for determinants of T-cell fitness and transformation as well as T-cell instructed dysfunctions of other immune cells. Such insights would advance our concepts of cancer biology and immunology. Common molecular links between T-LGLL and autoimmune diseases include activation of JAK/STAT signaling, proinflammatory cytokine environments, and antigen-driven immune responses. Current murine models address these mechanisms rather individually: JAK/STAT based systems replicate pathway activation, cytokine-driven models simulate inflammatory conditions, and RA models often mimic antigen stimulation. However, none of these fully captures the duality of clonal T-cell expansion and the complex immune dysregulations, inherent to T-LGLL. This review examines criteria for autochthonous in-vivo T-LGLL models and evaluates existing systems, identifying their strengths, limitations, and specific representations of clinico-pathologic aspects of LGLL. Prominent transgenic models, for example, not only manipulate the T-cell compartment but also indiscriminately alter the tumor microenvironment, impeding research on the specific role of elements of the LGLL micromilieu. We propose strategies to overcome such insufficiencies of present models. Overall, our critical appraisal emphasizes the need for novel comprehensive models that more faithfully integrate the key features of T-LGLL or for models that, by featuring specific pathogenetic aspects of the disease, would supplement existing incomplete systems. We expect such new model systems to aid in better understanding the cancer-immunity interface and in assessing novel therapeutic approaches for T-LGLL.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 4","pages":"792-804"},"PeriodicalIF":12.8,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-025-02553-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575261","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":"Living, not just surviving, with chronic myeloid leukemia – quality of life to the front of the line","authors":"Jeffrey H. Lipton, Delphine Rea","doi":"10.1038/s41375-025-02548-z","DOIUrl":"https://doi.org/10.1038/s41375-025-02548-z","url":null,"abstract":"<p>Chronic myeloid leukemia (CML) therapy has come a long way over the last three decades [1]. From a disease where curative options were available to a small percentage of the newly diagnosed patients and even then, with the possibility of significant treatment-related problems, survival is now close to that of age-matched controls in the general population if diagnosed in the chronic phase, patient compliance is good, and the drug is available [2]. Yes, we can debate improvements of a few percent being worth using very new and much more expensive drugs that are not available to much of the world, but we now have a disease where the disease-free-survival is better than overall survival, indicating that people are dying not unexpectedly, but not usually not from CML!</p><p>Major improvements in the management of CML, both in terms of drugs available and without a doubt, our ability to monitor disease response or loss of response with molecular technology, are now routinely available and have made this easier on both the patient and the treating physician [3]. One would think that this along with the survival improvement, would be the issue that would give patients the most content. Recent patient-directed surveys have indicated that this may not be true and that what we as physicians consider to be the most important, are often not the same for patients.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"16 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546212","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":"Management of children and adolescents with chronic myeloid leukemia in chronic phase: International pediatric chronic myeloid leukemia expert panel recommendations","authors":"Frédéric Millot,&nbsp;Mirella Ampatzidou,&nbsp;Nirmalya Roy Moulik,&nbsp;Sanjay Tewari,&nbsp;Alaa Elhaddad,&nbsp;Mahmoud Hammad,&nbsp;Herbert Pichler,&nbsp;Thomas Lion,&nbsp;Athanasios Tragiannidis,&nbsp;Haruko Shima,&nbsp;Wenbin An,&nbsp;Wenyu Yang,&nbsp;Axel Karow,&nbsp;Roula Farah,&nbsp;Maaike Luesink,&nbsp;Michael Dworzak,&nbsp;Stephanie Sembill,&nbsp;Barbara De Moerloose,&nbsp;Petr Sedlacek,&nbsp;Kirk R. Schultz,&nbsp;Krzysztof Kalwak,&nbsp;Birgitta Versluys,&nbsp;Uma Athale,&nbsp;Nobuko Hijiya,&nbsp;Markus Metzler,&nbsp;Meinolf Suttorp","doi":"10.1038/s41375-025-02543-4","DOIUrl":"10.1038/s41375-025-02543-4","url":null,"abstract":"The treatment strategy for children and adolescents with chronic myeloid leukemia in the chronic phase (CML-CP) has evolved from allogeneic hematopoietic stem cell transplantation (HSCT) to tyrosine kinase inhibitors (TKIs). With the advent of next-generation TKIs and new targeted therapies in the CML field, an international pediatric CML expert panel provides recommendations based on the medical literature (including previous pediatric guidelines), national standards, and treatment principles used in adults with CML-CP. Recommendations include diagnosis of the disease and details on managing the initial steps of care of children and adolescents with newly diagnosed CML-CP, including complications such as leukostasis. The treatment recommendations are based on the initiation of therapy with a first- or second-generation TKI according to the allocated European Treatment and Outcome Study (EUTOS) long-term survival score risk group of the patient. The subsequent steps are based on the results of recommended monitoring which can justify a switch to another TKI or a drug in development if there is resistance or toxicity. The panel also provides recommendations regarding the discontinuation criteria for TKIs in children and adolescents in sustained deep molecular response. Allogeneic HSCT is not recommended as the first-line of treatment for children with CML-CP but is to be considered in case of progression to the advanced phase or failure of several lines of treatment. The present treatment and management recommendations are intended to provide advice to clinicians in view of optimizing the care and the outcome of children and adolescents with CML-CP.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 4","pages":"779-791"},"PeriodicalIF":12.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-025-02543-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546213","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":"Implications of lymphocyte kinetics after chimeric antigen receptor T cell therapy for multiple myeloma","authors":"Sarah Dingli,&nbsp;Paul Rothweiler,&nbsp;Moritz Binder,&nbsp;Joselle Cook,&nbsp;Morie A. Gertz,&nbsp;Suzanne Hayman,&nbsp;Prashant Kapoor,&nbsp;Taxiarchis Kourelis,&nbsp;Shaji K. Kumar,&nbsp;Mustaqeem Siddiqui,&nbsp;Rahma Warsame,&nbsp;Yi Lin,&nbsp;Arthur G. Erdman,&nbsp;David Dingli","doi":"10.1038/s41375-025-02547-0","DOIUrl":"10.1038/s41375-025-02547-0","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 4","pages":"1005-1008"},"PeriodicalIF":12.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-025-02547-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546626","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":"CD34+CD38- leukemia stem cells predict clinical outcomes in acute myeloid leukemia patients treated non-intensively with hypomethylating agents","authors":"Tom Reuvekamp,&nbsp;Lok Lam Ngai,&nbsp;Daphne den Hartog,&nbsp;Jannemieke Carbaat-Ham,&nbsp;Mona M. H. E. Fayed,&nbsp;Willemijn J. Scholten,&nbsp;Tim R. Mocking,&nbsp;Dana A. Chitu,&nbsp;Thomas Pabst,&nbsp;Saskia K. Klein,&nbsp;Georg Stussi,&nbsp;Laimonas Griskevicius,&nbsp;Dimitri Breems,&nbsp;Danielle van Lammeren-Venema,&nbsp;Rinske Boersma,&nbsp;Gert J. Ossenkoppele,&nbsp;Arjan A. van de Loosdrecht,&nbsp;Costa Bachas,&nbsp;Gerwin Huls,&nbsp;David C. de Leeuw,&nbsp;Jacqueline Cloos","doi":"10.1038/s41375-025-02539-0","DOIUrl":"10.1038/s41375-025-02539-0","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 4","pages":"972-975"},"PeriodicalIF":12.8,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-025-02539-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507049","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":"Daratumumab/lenalidomide/dexamethasone in transplant-ineligible newly diagnosed myeloma: MAIA long-term outcomes","authors":"Thierry Facon,&nbsp;Philippe Moreau,&nbsp;Katja Weisel,&nbsp;Hartmut Goldschmidt,&nbsp;Saad Z. Usmani,&nbsp;Ajai Chari,&nbsp;Torben Plesner,&nbsp;Robert Z. Orlowski,&nbsp;Nizar Bahlis,&nbsp;Supratik Basu,&nbsp;Cyrille Hulin,&nbsp;Hang Quach,&nbsp;Michael O’Dwyer,&nbsp;Aurore Perrot,&nbsp;Caroline Jacquet,&nbsp;Christopher P. Venner,&nbsp;Noopur Raje,&nbsp;Mourad Tiab,&nbsp;Margaret Macro,&nbsp;Laurent Frenzel,&nbsp;Xavier Leleu,&nbsp;Gordon Cook,&nbsp;George Wang,&nbsp;Huiling Pei,&nbsp;Maria Krevvata,&nbsp;Robin Carson,&nbsp;Fredrik Borgsten,&nbsp;Shaji K. Kumar","doi":"10.1038/s41375-024-02505-2","DOIUrl":"10.1038/s41375-024-02505-2","url":null,"abstract":"In the MAIA study, daratumumab plus lenalidomide and dexamethasone (D-Rd) improved progression-free survival (PFS) and overall survival (OS) versus lenalidomide and dexamethasone (Rd) alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). We report updated efficacy and safety from MAIA (median follow-up, 64.5 months), including a subgroup analysis by patient age (&lt;70, ≥70 to &lt;75, ≥75, and ≥80 years). Overall, 737 transplant-ineligible patients with NDMM were randomized 1:1 to D-Rd or Rd. The primary endpoint, PFS, was improved with D-Rd versus Rd (median, 61.9 vs 34.4 months; hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.45–0.67; P &lt; 0.0001). Median OS was not reached in the D-Rd group versus 65.5 months in the Rd group (HR, 0.66; 95% CI, 0.53–0.83; P = 0.0003); estimated 60-month OS rates were 66.6% and 53.6%, respectively. D-Rd achieved higher rates of complete response or better (≥CR; 51.1% vs 30.1%), minimal residual disease (MRD) negativity (32.1% vs 11.1%), and sustained MRD negativity (≥18 months: 16.8% vs 3.3%) versus Rd (all P &lt; 0.0001). D-Rd demonstrated clinically meaningful efficacy benefits across age groups. No new safety concerns were observed. Updated results (median follow-up, &gt;5 years) continue to support frontline use of D-Rd in transplant-ineligible patients with NDMM.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 4","pages":"942-950"},"PeriodicalIF":12.8,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02505-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507441","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":"Long term results of venetoclax combined with FLAG-IDA induction and consolidation for newly diagnosed and relapsed or refractory acute myeloid leukemia","authors":"Courtney D. DiNardo,&nbsp;Wei-Ying Jen,&nbsp;Koichi Takahashi,&nbsp;Tapan M. Kadia,&nbsp;Sanam Loghavi,&nbsp;Naval G. Daver,&nbsp;Lianchun Xiao,&nbsp;Patrick K. Reville,&nbsp;Ghayas C. Issa,&nbsp;Nicholas J. Short,&nbsp;Koji Sasaki,&nbsp;Sa A. Wang,&nbsp;Jillian K. Mullin,&nbsp;Sherry Pierce,&nbsp;Corey Bradley,&nbsp;Gautam Borthakur,&nbsp;Abhishek Maiti,&nbsp;Yesid Alvarado,&nbsp;Naveen Pemmaraju,&nbsp;Alessandra Ferrajoli,&nbsp;Mahesh Swaminathan,&nbsp;Maro Ohanian,&nbsp;Hussein A. Abbas,&nbsp;Danielle Hammond,&nbsp;Jan Burger,&nbsp;Fadi Haddad,&nbsp;Guillermo Montalban-Bravo,&nbsp;Kelly Chien,&nbsp;Lucia Masarova,&nbsp;Musa Yilmaz,&nbsp;Nitin Jain,&nbsp;Michael Andreeff,&nbsp;Guillermo Garcia-Manero,&nbsp;Steven Kornblau,&nbsp;Farhad Ravandi,&nbsp;Elias Jabbour,&nbsp;Marina Y. Konopleva,&nbsp;Hagop M. Kantarjian","doi":"10.1038/s41375-025-02531-8","DOIUrl":"10.1038/s41375-025-02531-8","url":null,"abstract":"Intensive chemotherapy remains the standard for newly diagnosed (ND) acute myeloid leukemia (AML); however, relapse risk remains high. Additionally, most patients with relapsed/refractory (RR) AML have poor outcomes. We report the long-term experience of 138 patients, 77 ND and 61 RR, treated with FLAG-IDA in combination with venetoclax. In the ND cohort, the overall response rate (ORR) was 97%, with a composite complete remission (CRc) rate of 95% and undetectable measurable residual disease (MRD) status by flow cytometry in 90%. The 3-year OS and EFS rates were 66 and 64%, respectively. Outcomes were similar across European LeukemiaNet (ELN) 2022 risk groups. Sixty-four percent transitioned to allogeneic hematopoietic stem cell transplantation (allo-SCT) in CR1. In the RR cohort, the ORR was 67%; CRc rate 41% and flow negative MRD rate 74%; 57% transitioned to allo-SCT. The patients with RR AML in first salvage with wild-type TP53 status had particularly favorable outcomes, with an ORR of 79%, CRc rate of 74% (76% MRD undetectable) and 3-year OS rate of 51%. Infectious and hematologic adverse events were common, with low 30- and 60-day mortality similar to other intensive chemotherapy regimens. FLAG-IDA + VEN is effective for remission induction in both ND and RR AML. ClinicalTrials.gov Identifier: NCT03214562","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 4","pages":"854-863"},"PeriodicalIF":12.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-025-02531-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143486352","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":"Challenges determining the best target duration of deep molecular response after which to attempt achieving therapy-free remission in chronic myeloid leukaemia","authors":"Xiaowen Gong,&nbsp;Xiaolin Zhai,&nbsp;Qiujin Shen,&nbsp;Robert Peter Gale,&nbsp;Junren Chen","doi":"10.1038/s41375-025-02540-7","DOIUrl":"10.1038/s41375-025-02540-7","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 4","pages":"810-815"},"PeriodicalIF":12.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-025-02540-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485817","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":"Comparison of recognition of symptom burden in MPN between patient- and physician-reported assessment – an intraindividual analysis by the German Study Group for MPN (GSG-MPN)","authors":"Kirsi Manz,&nbsp;Florian H. Heidel,&nbsp;Steffen Koschmieder,&nbsp;Rudolf Schlag,&nbsp;Jörg Lipke,&nbsp;Frank Stegelmann,&nbsp;Martin Griesshammer,&nbsp;Martine Klausmann,&nbsp;Carl Crodel,&nbsp;Andreas Hochhaus,&nbsp;Holger Schulz,&nbsp;Joachim R. Göthert,&nbsp;Haifa Al-Ali,&nbsp;Heiko Becker,&nbsp;Andreas Reiter,&nbsp;Gernot Beutel,&nbsp;Kim Kricheldorf,&nbsp;Tim H. Brümmendorf,&nbsp;Wolfgang Hoffmann,&nbsp;Konstanze Döhner,&nbsp;Susanne Isfort,&nbsp;On behalf of the German Study Group for Myeloproliferative Neoplasms (GSG-MPN)","doi":"10.1038/s41375-025-02524-7","DOIUrl":"10.1038/s41375-025-02524-7","url":null,"abstract":"Myeloproliferative neoplasms (MPN) are associated with a variety of symptoms that severely impact patients’ quality of life and ability to perform daily activities. Recent studies showed differences in the perception of physician- versus patient-reported symptom burden. However, studies directly comparing patient- and physician-reported ratings are lacking. Here, a retrospective analysis on symptom burden of 3979 MPN patients of the Bioregistry of the German Study Group for MPN was conducted to intra-individually compare physician and patient reports collected at the same time. Cohen’s kappa was calculated to assess the degree of agreement between patient and physician reports. Factors influencing baseline symptom severity were identified using linear regression and adjusted Cox models were calculated to investigate the effect of symptom burden on survival. MPN patients had a high symptom burden, which neither decreased over time nor upon cytoreductive therapy. All symptoms were more frequently reported by patients compared to physicians. Agreement remained low and only slightly improved when considering a higher threshold for patient symptom severity. Patients with severe symptom burden had inferior survival compared to patients with less severe symptoms. Assessment of symptom burden in MPN is therefore insufficient and patient-reported outcome tools need to be implemented into clinical routine.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 4","pages":"864-875"},"PeriodicalIF":12.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-025-02524-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485818","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":"Haploinsufficiency of miR-143 and miR-145 reveal targetable dependencies in resistant del(5q) myelodysplastic neoplasm","authors":"Nadia Gharaee,&nbsp;Joanna Wegrzyn-Woltosz,&nbsp;Jihong Jiang,&nbsp;Vijay Suresh Akhade,&nbsp;Joshua Bridgers,&nbsp;Ryan J. Stubbins,&nbsp;Devendra Hiwase,&nbsp;Monika M. Kutyna,&nbsp;Onyee Chan,&nbsp;Rami Komrokji,&nbsp;Eric Padron,&nbsp;Yu Deng,&nbsp;Gary Cole,&nbsp;Patricia Umlandt,&nbsp;Megan Fuller,&nbsp;Ada Kim,&nbsp;Aly Karsan","doi":"10.1038/s41375-025-02537-2","DOIUrl":"10.1038/s41375-025-02537-2","url":null,"abstract":"Myelodysplastic neoplasms (MDS) are stem cell disorders characterized by ineffective hematopoiesis and risk of transformation to acute myeloid leukemia (AML). Chromosomal alterations are frequent in MDS, with interstitial deletion of chromosome 5q (del(5q)) being the most common. Lenalidomide is the current first-line treatment for del(5q) MDS and its efficacy relies on degradation of CK1α which is encoded by the CSNK1A1 gene located in the commonly deleted region (CDR) of chromosome 5q. However, lenalidomide-resistance is common, often secondary to loss-of-function mutations in TP53 or RUNX1. The CDR in del(5q) harbors several genes, including noncoding miRNAs, the loss of which contribute to disease phenotypes. miR-143 and miR-145 are located within the del(5q) CDR, but precise understanding of their role in human hematopoiesis and in the pathogenesis of del(5q) MDS is lacking. Here we provide evidence that deficiency of miR-143 and miR-145 plays a role in clonal expansion of del(5q) MDS. We show that insulin-like growth factor 1 receptor (IGF-1R) is a direct target of both miR-143 and miR-145. Our data demonstrate that IGF-1R inhibition reduces proliferation and viability of del(5q) cells in vitro and in vivo, and that lenalidomide-resistant del(5q) MDS cells depleted of either TP53 or RUNX1 are sensitive to IGF-1R inhibition. Resistant del(5q) MDS-L cells, as well as primary MDS marrow cells, are also sensitive to targeting of IGF-1R-related dependencies in del(5q) MDS, which include the Abl and MAPK signaling pathways. This work thus provides potential new therapeutic avenues for lenalidomide-resistant del(5q) MDS.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 4","pages":"917-928"},"PeriodicalIF":12.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-025-02537-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485820","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}