Leukemia最新文献

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Predicting antigen-specific T-cell immunity against Wilms tumor 1 in hematologic cancer 预测血液癌中针对Wilms肿瘤1抗原特异性t细胞免疫
IF 11.4 1区 医学
Leukemia Pub Date : 2025-08-22 DOI: 10.1038/s41375-025-02727-y
Brittany L. Ford, Emmi Jokinen, Jani Huuhtanen, Sofia Forstén, Jay Klievink, Gabriella Antignani, Oscar Brück, Vincenzo Cerullo, Karita Peltonen, Satu Mustjoki
{"title":"Predicting antigen-specific T-cell immunity against Wilms tumor 1 in hematologic cancer","authors":"Brittany L. Ford, Emmi Jokinen, Jani Huuhtanen, Sofia Forstén, Jay Klievink, Gabriella Antignani, Oscar Brück, Vincenzo Cerullo, Karita Peltonen, Satu Mustjoki","doi":"10.1038/s41375-025-02727-y","DOIUrl":"https://doi.org/10.1038/s41375-025-02727-y","url":null,"abstract":"<p>Wilms tumor 1 (WT1) is a tumor-associated antigen expressed in solid tumors and hematological malignancies. T-cell immunotherapies targeting WT1 are currently under development. To analyze endogenous T-cell responses against WT1, we trained computational models capable of detecting WT1-specific T-cell responses from T-cell receptor (TCR) sequencing data. We peptide-pulsed healthy donor and acute myeloid leukemia (AML) patient samples with VLDFAPPGA (VLD, WT1<sub>37-45</sub>) and RMFPNAPYL (RMF, WT1<sub>126-134</sub>) peptides, then sequenced the WT1 dextramer-positive CD8 + T-cells with single-cell RNA + TCRαβ sequencing. The TCRGP machine-learning TCR-classification method was trained with epitope-specific and control TCR repertoires, and we obtained AUROC values of 0.74 (VLD) and 0.75 (RMF), allowing reliable identification of WT1-specific T-cells. In bulk TCRβ sequenced patient samples (AML n = 21, chronic myeloid leukemia (CML) n = 26, and myelodysplastic syndrome n = 25), the median WT1-specific T-cell abundance was similar to healthy controls, but their VLD and RMF-specific TCR repertoires exhibited higher clonality with two patients presenting up to 13% of WT1-specific T-cells. ScRNA+TCRαβ sequencing of AML bone marrow T-cells revealed that WT1-specific T-cells predominantly exhibit an effector or terminal effector memory phenotype. In conclusion, our novel computational models enable large-scale WT1-specific T-cell identification from TCR sequencing datasets and leukemia-antigen-specific immune response monitoring.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"22 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899306","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}
引用次数: 0
Unraveling the molecular landscape of Erdheim–Chester disease: new insights from methylome and transcriptome integration 揭示厄德海姆-切斯特病的分子景观:来自甲基组和转录组整合的新见解
IF 11.4 1区 医学
Leukemia Pub Date : 2025-08-21 DOI: 10.1038/s41375-025-02742-z
Miriam Cerván-Martín, Francesco Pegoraro, Javier Martínez-López, Inmaculada Rodriguez-Martin, Ana Márquez, Lourdes Ortiz-Fernández, Marialbert Acosta-Herrera, Martin Kerick, Eduardo Andrés-León, Francesco Catamerò, Matthias Papo, Fleur Cohen-Aubart, Zahir Amoura, Julien Haroche, Augusto Vaglio, Javier Martín
{"title":"Unraveling the molecular landscape of Erdheim–Chester disease: new insights from methylome and transcriptome integration","authors":"Miriam Cerván-Martín, Francesco Pegoraro, Javier Martínez-López, Inmaculada Rodriguez-Martin, Ana Márquez, Lourdes Ortiz-Fernández, Marialbert Acosta-Herrera, Martin Kerick, Eduardo Andrés-León, Francesco Catamerò, Matthias Papo, Fleur Cohen-Aubart, Zahir Amoura, Julien Haroche, Augusto Vaglio, Javier Martín","doi":"10.1038/s41375-025-02742-z","DOIUrl":"https://doi.org/10.1038/s41375-025-02742-z","url":null,"abstract":"<p>Erdheim–Chester Disease (ECD) is a rare histiocytosis characterized by a wide spectrum of clinical manifestations. Although somatic mutations have been involved in ECD, its etiology remains poorly understood. This study aimed to identify novel molecular mechanisms involved in ECD through the first integrated methylome and transcriptome analysis. Peripheral blood samples were collected from 137 ECD patients and 410 controls. Genome-wide DNA methylation and transcriptome analyses were performed, followed by functional in silico studies using different online bioinformatics tools. Subsequently, methylome and transcriptome data were integrated, and a drug repurposing approach was undertaken. Our results revealed 2511 differentially methylated positions and 1484 differentially expressed genes associated with ECD. The integrative analysis identified 46 alterations in DNA methylation patterns that regulate the expression levels of 29 altered genes in ECD patients, highlighting key genes involved in immune response and tumorigenesis. Remarkably, our results identified B cells and NF-kB signaling pathway as novel contributors of ECD pathogenesis. Finally, the drug repurposing analysis identified potential therapeutic options for ECD patients. In conclusion, this study represents an important advance in understanding the molecular basis of ECD, proposing novel cell types and pathways involved in ECD pathogenesis and suggesting new avenues for clinical management.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"36 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899309","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}
引用次数: 0
Germline Jak2-R1063H mutation interferes with normal hematopoietic development and increases risk of thrombosis and leukemic transformation 种系Jak2-R1063H突变干扰正常的造血发育,增加血栓形成和白血病转化的风险
IF 11.4 1区 医学
Leukemia Pub Date : 2025-08-21 DOI: 10.1038/s41375-025-02737-w
Veronika Zimolova, Monika Burocziova, Linda Berkova, Srdjan Grusanovic, Jan Gursky, Lubos Janotka, Petr Kasparek, Alena Pecinova, David Kundrat, Dusan Hrckulak, Jakub Onhajzer, Ivana Jeziskova, Lucie Nekvindova, Barbora Weinbergerova, Sarka Pospisilova, Michael Doubek, Meritxell Alberich-Jorda, Vladimir Korinek, Vladimir Divoky, Lucie Lanikova
{"title":"Germline Jak2-R1063H mutation interferes with normal hematopoietic development and increases risk of thrombosis and leukemic transformation","authors":"Veronika Zimolova, Monika Burocziova, Linda Berkova, Srdjan Grusanovic, Jan Gursky, Lubos Janotka, Petr Kasparek, Alena Pecinova, David Kundrat, Dusan Hrckulak, Jakub Onhajzer, Ivana Jeziskova, Lucie Nekvindova, Barbora Weinbergerova, Sarka Pospisilova, Michael Doubek, Meritxell Alberich-Jorda, Vladimir Korinek, Vladimir Divoky, Lucie Lanikova","doi":"10.1038/s41375-025-02737-w","DOIUrl":"https://doi.org/10.1038/s41375-025-02737-w","url":null,"abstract":"<p>The acquired <i>JAK2</i>-V617F mutation plays a causal role in myeloproliferative neoplasms (MPN). Weakly activating <i>JAK2</i> germline variants have been associated with MPN risk, but the underlying mechanisms remain unclear. We previously identified the <i>JAK2</i>-R1063H germline variant, which contributes to hereditary MPN and increased disease severity in essential thrombocythemia. Here, we studied alterations in hematopoiesis in <i>Jak2</i>-R1063H knock-in mice. The <i>Jak2</i>-R1063H mouse cohort exhibited increased mortality, stimulated thrombopoiesis and elevated D-dimers levels, indicative of thrombotic complications. Bone marrow analysis revealed myeloid bias, enhanced megakaryopoiesis and activation of inflammatory signaling. Transcriptional and functional assays of hematopoietic stem cells suggested their accelerated aging and functional decline. The Egr1 transcriptional network, including the <i>Thbs1</i> gene, progressively increased in aging mice, reinforcing alterations initiated by Jak2/Stat signaling. In murine acute myelogenous leukemia models, the <i>Jak2</i>-R1063H cooperated with a driver oncogene in promoting leukemogenesis. Germline <i>JAK2</i>-R1063H was found in 10 of 200 MPN patients from local hematology centers, with a higher minor allele frequency compared to healthy controls. Patients harboring <i>JAK2</i>-R1063H variant exhibited an increased incidence of thrombotic complications and disease progression with shortened survival. In conclusion, our findings identify the <i>JAK2</i>-R1063H germline variant as a risk factor for MPN development, thrombotic complications, and leukemic transformation.</p><figure><p>Our study, which involves a mouse model and a cohort of 200 MPN patients, characterizes the <i>JAK2</i>-R1063H germline mutation as a risk factor for MPN development, thrombotic complications, and leukemic transformation. These findings may have important clinical implications for managing MPN patients carrying the <i>JAK2</i>-R1063H germline variant.</p></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"15 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899308","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}
引用次数: 0
Targeting p16INK4a-mediated cellular senescence as a therapeutic strategy for FLT3-ITD-driven acute myeloid leukemia 靶向p16ink4a介导的细胞衰老作为flt3 - itd驱动的急性髓系白血病的治疗策略
IF 11.4 1区 医学
Leukemia Pub Date : 2025-08-21 DOI: 10.1038/s41375-025-02743-y
Jiarui Zheng, Linlin Jin, Yunlong Chen, Yongjuan Duan, Suyu Zong, Peng Wu, Xiaofan Zhu, Wenyu Yang, Tianyuan Hu, Yingchi Zhang
{"title":"Targeting p16INK4a-mediated cellular senescence as a therapeutic strategy for FLT3-ITD-driven acute myeloid leukemia","authors":"Jiarui Zheng, Linlin Jin, Yunlong Chen, Yongjuan Duan, Suyu Zong, Peng Wu, Xiaofan Zhu, Wenyu Yang, Tianyuan Hu, Yingchi Zhang","doi":"10.1038/s41375-025-02743-y","DOIUrl":"https://doi.org/10.1038/s41375-025-02743-y","url":null,"abstract":"<p>Cellular senescence serves as a critical tumor-suppressive mechanism across various cancer types, yet its role in <i>FLT3</i>-ITD-positive acute myeloid leukemia (AML) remains poorly understood. Through the analysis of multiple sequencing datasets, we identified that <i>FLT3</i>-ITD-positive patients with low <i>p16</i><sup><i>INK4a</i></sup> expression have significantly worse prognoses. Consistent with these clinical findings, knockout of <i>p16</i><sup><i>INK4a</i></sup> in mice was shown to accelerate <i>FLT3</i>-ITD AML onset. Mechanistic investigations further revealed that the <i>FLT3</i>-ITD mutation suppresses <i>p16</i><sup><i>INK4a</i></sup> expression via the STAT5A-E2F3-EZH2 signaling axis. This downregulation of <i>p16</i><sup><i>INK4a</i></sup> allows cells to evade senescence, thereby promoting increased malignancy and establishing a positive feedback loop that exacerbates disease progression. This mechanism provides a molecular explanation for the poorer long-term survival observed in this patient subset. Furthermore, the <i>FLT3</i>-ITD-STAT5A/E2F3/EZH2-<i>p16</i><sup><i>INK4a</i></sup> axis identified in this study represents a promising therapeutic target for addressing refractory <i>FLT3</i>-ITD AML with low <i>p16</i><sup><i>INK4a</i></sup> expression.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"21 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899307","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}
引用次数: 0
Progressive T cell defects correlate with disease outcome in high-count monoclonal B-cell lymphocytosis 进行性T细胞缺陷与高计数单克隆b细胞淋巴细胞增多症的疾病结局相关
IF 13.4 1区 医学
Leukemia Pub Date : 2025-08-20 DOI: 10.1038/s41375-025-02689-1
Sameer A. Parikh, Nikolaos Ioannou, Alan G. Ramsay, Justin C. Boysen, Saad S. Kenderian, Kari G. Rabe, Sutapa Sinha, Esteban Braggio, Kay L. Medina, Susan L. Slager, Tait D. Shanafelt, Neil E. Kay
{"title":"Progressive T cell defects correlate with disease outcome in high-count monoclonal B-cell lymphocytosis","authors":"Sameer A. Parikh,&nbsp;Nikolaos Ioannou,&nbsp;Alan G. Ramsay,&nbsp;Justin C. Boysen,&nbsp;Saad S. Kenderian,&nbsp;Kari G. Rabe,&nbsp;Sutapa Sinha,&nbsp;Esteban Braggio,&nbsp;Kay L. Medina,&nbsp;Susan L. Slager,&nbsp;Tait D. Shanafelt,&nbsp;Neil E. Kay","doi":"10.1038/s41375-025-02689-1","DOIUrl":"10.1038/s41375-025-02689-1","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 10","pages":"2551-2554"},"PeriodicalIF":13.4,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899092","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}
引用次数: 0
A scholar of blood and beauty: remembering Prof. Jacques-Louis Binet (1932–2024) 血与美的学者:缅怀雅克-路易斯·比奈教授(1932-2024)。
IF 13.4 1区 医学
Leukemia Pub Date : 2025-08-15 DOI: 10.1038/s41375-025-02726-z
Thomas J. Kipps
{"title":"A scholar of blood and beauty: remembering Prof. Jacques-Louis Binet (1932–2024)","authors":"Thomas J. Kipps","doi":"10.1038/s41375-025-02726-z","DOIUrl":"10.1038/s41375-025-02726-z","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 9","pages":"2309-2310"},"PeriodicalIF":13.4,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02726-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144857691","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}
引用次数: 0
Distinct stromal cell populations define the B-cell acute lymphoblastic leukemia microenvironment 不同的基质细胞群定义了b细胞急性淋巴细胞白血病微环境
IF 11.4 1区 医学
Leukemia Pub Date : 2025-08-15 DOI: 10.1038/s41375-025-02734-z
Mauricio N. Ferrao Blanco, Bexultan Kazybay, Mirjam Belderbos, Olaf Heidenreich, Hermann Josef Vormoor
{"title":"Distinct stromal cell populations define the B-cell acute lymphoblastic leukemia microenvironment","authors":"Mauricio N. Ferrao Blanco, Bexultan Kazybay, Mirjam Belderbos, Olaf Heidenreich, Hermann Josef Vormoor","doi":"10.1038/s41375-025-02734-z","DOIUrl":"https://doi.org/10.1038/s41375-025-02734-z","url":null,"abstract":"<p>The bone marrow microenvironment plays a critical role in B-cell acute lymphoblastic leukemia (B-ALL) progression, yet its cellular heterogeneity remains poorly understood. Using single-cell RNA sequencing on patient-derived bone marrow aspirates from pediatric B-ALL patients, we identified two distinct mesenchymal stromal cell (MSC) populations: early mesenchymal progenitors and adipogenic progenitors. Spatial transcriptomic analysis further revealed the localization of these cell types and identified a third stromal population, osteogenic-lineage cells, exclusively present in the bone biopsy. Functional ex vivo assays using sorted stromal populations derived from B-ALL patient bone marrow aspirates demonstrated that both early mesenchymal and adipogenic progenitors secrete key niche-supportive factors, including CXCL12 and Osteopontin, and support leukemic cell survival and chemoresistance. Transcriptomic profiling revealed that B-ALL cells interact differently with stromal subtypes. Notably, adipogenic progenitors, but not early mesenchymal progenitors, provide support to leukemic cells through interleukin-7 and VCAM1 signaling. Stromal cells from B-ALL patients exhibited an enhanced adipogenic differentiation capacity compared to healthy controls. Moreover, co-culture experiments showed that B-ALL cells induce adipogenic differentiation in healthy MSCs through a cell contact-dependent mechanism. Adipogenic progenitors were also enriched in relapse samples, implicating them in disease progression. These findings highlight the complexity of the B-ALL microenvironment and identify different specialized stromal niches with which the leukemic cells can engage.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"8 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144851325","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}
引用次数: 0
Outcomes of adult patients with newly diagnosed IDH-mutated AML treated with intensive chemotherapy and venetoclax 新诊断idh突变AML的成年患者接受强化化疗和venetoclax治疗的结果
IF 13.4 1区 医学
Leukemia Pub Date : 2025-08-14 DOI: 10.1038/s41375-025-02733-0
Jennifer Croden, Wei-Ying Jen, Jennifer Marvin-Peek, Lianchun Xiao, Ian M. Bouligny, Sanam Loghavi, Gautam Borthakur, Naval G. Daver, Hussein A. Abbas, Koichi Takahashi, Koji Sasaki, Naveen Pemmaraju, Nicholas J. Short, Danielle Hammond, Elias Jabbour, Lucia Masarova, Kelly S. Chien, Ghayas C. Issa, Guillermo Montalban-Bravo, Musa Yilmaz, Abhishek Maiti, Yesid Alvarado-Valero, Guillermo Garcia-Manero, Farhad Ravandi, Marina Y. Konopleva, Hagop M. Kantarjian, Tapan M. Kadia, Courtney D. DiNardo
{"title":"Outcomes of adult patients with newly diagnosed IDH-mutated AML treated with intensive chemotherapy and venetoclax","authors":"Jennifer Croden,&nbsp;Wei-Ying Jen,&nbsp;Jennifer Marvin-Peek,&nbsp;Lianchun Xiao,&nbsp;Ian M. Bouligny,&nbsp;Sanam Loghavi,&nbsp;Gautam Borthakur,&nbsp;Naval G. Daver,&nbsp;Hussein A. Abbas,&nbsp;Koichi Takahashi,&nbsp;Koji Sasaki,&nbsp;Naveen Pemmaraju,&nbsp;Nicholas J. Short,&nbsp;Danielle Hammond,&nbsp;Elias Jabbour,&nbsp;Lucia Masarova,&nbsp;Kelly S. Chien,&nbsp;Ghayas C. Issa,&nbsp;Guillermo Montalban-Bravo,&nbsp;Musa Yilmaz,&nbsp;Abhishek Maiti,&nbsp;Yesid Alvarado-Valero,&nbsp;Guillermo Garcia-Manero,&nbsp;Farhad Ravandi,&nbsp;Marina Y. Konopleva,&nbsp;Hagop M. Kantarjian,&nbsp;Tapan M. Kadia,&nbsp;Courtney D. DiNardo","doi":"10.1038/s41375-025-02733-0","DOIUrl":"10.1038/s41375-025-02733-0","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 10","pages":"2538-2541"},"PeriodicalIF":13.4,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840113","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}
引用次数: 0
Unraveling the impact of crizotinib to promote megakaryopoiesis for alleviating thrombocytopenia in myelodysplastic neoplasms 阐明克唑替尼促进巨核生成以减轻骨髓增生异常肿瘤中血小板减少症的影响
IF 11.4 1区 医学
Leukemia Pub Date : 2025-08-14 DOI: 10.1038/s41375-025-02729-w
Hiroki Kobayashi, Yuta Komizo, Nanami Watanabe, Yu Miyata, Yoshiya Ohnuma, Yasushige Kamimura-Aoyagi, Kanako Yuki, Yoshihiro Hayashi, Minoru Yoshida, Yuka Harada, Hironori Harada
{"title":"Unraveling the impact of crizotinib to promote megakaryopoiesis for alleviating thrombocytopenia in myelodysplastic neoplasms","authors":"Hiroki Kobayashi, Yuta Komizo, Nanami Watanabe, Yu Miyata, Yoshiya Ohnuma, Yasushige Kamimura-Aoyagi, Kanako Yuki, Yoshihiro Hayashi, Minoru Yoshida, Yuka Harada, Hironori Harada","doi":"10.1038/s41375-025-02729-w","DOIUrl":"https://doi.org/10.1038/s41375-025-02729-w","url":null,"abstract":"<p>Current therapeutic options for myelodysplastic neoplasms (MDS)-associated thrombocytopenia are limited. Megakaryocyte maturation might be an innovative therapeutic strategy because its dysregulation profoundly contributes to MDS pathogenesis. Here, we identified crizotinib, a clinically approved anti-cancer drug for anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer, as a potent inducer of megakaryocyte maturation. We demonstrated that crizotinib effectively induced polyploidization to increase the platelet-producing capacity of megakaryocytes derived from an MDS murine model and MDS patients by targeting Aurora kinases rather than its canonical targets, ALK/ROS1/c-MET. Importantly, crizotinib administration substantially ameliorated thrombocytopenia in our preclinical model. Our findings underscore the remarkable potential of crizotinib for drug repurposing and offer a novel therapeutic strategy for MDS patients with thrombocytopenia facing health-related quality of life concerns.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"15 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840036","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}
引用次数: 0
Underlying biology, challenges and emergent concepts in the treatment of relapsed and refractory pediatric T-cell acute lymphoblastic leukemia 复发和难治性儿童t细胞急性淋巴细胞白血病治疗的潜在生物学、挑战和新兴概念
IF 11.4 1区 医学
Leukemia Pub Date : 2025-08-14 DOI: 10.1038/s41375-025-02723-2
Patrícia Amaral, Rhona Christie, Daisy O. F. Gresham, Emma J. M. Lucas, Luyao Kevin Xu, Lena Behrmann, Jonathan Bond, Sofie Degerman, Frederik W. van Delft, Steven Goossens, Melanie Hagleitner, Chris Halsey, Nicholas Jones, Tim Lammens, Frank N. van Leeuwen, Marc R. Mansour, Panagiotis Ntziachristos, David O’Connor, João T. Barata
{"title":"Underlying biology, challenges and emergent concepts in the treatment of relapsed and refractory pediatric T-cell acute lymphoblastic leukemia","authors":"Patrícia Amaral, Rhona Christie, Daisy O. F. Gresham, Emma J. M. Lucas, Luyao Kevin Xu, Lena Behrmann, Jonathan Bond, Sofie Degerman, Frederik W. van Delft, Steven Goossens, Melanie Hagleitner, Chris Halsey, Nicholas Jones, Tim Lammens, Frank N. van Leeuwen, Marc R. Mansour, Panagiotis Ntziachristos, David O’Connor, João T. Barata","doi":"10.1038/s41375-025-02723-2","DOIUrl":"https://doi.org/10.1038/s41375-025-02723-2","url":null,"abstract":"<p>Relapsed and refractory disease in children with T-cell acute lymphoblastic leukemia (R/R T-ALL) remains a major clinical challenge. Outcomes for children who relapse or exhibit resistance to initial treatments are dismal, with survival rates frequently below 25% despite aggressive therapy. To minimize toxicities and improve outcomes, individualized precision medicine approaches targeting the underlying biology of R/R T-ALL are especially important, considering that T-ALL is characterized by genetic, epigenetic and posttranscriptional heterogeneity, and organ and niche specificities (e.g. the central nervous system), all of which underlie disease progression and therapy resistance. Here, we summarize the current understanding of the complexity of pediatric T-ALL biology and how such knowledge may be clinically leveraged, emphasizing the need for innovative therapeutic routes to improve outcomes for children with R/R T-ALL. Emerging approaches that hold promise or show palpable results include proteasome inhibitors, BCL-2 antagonists, and JAK (for JAK- and IL-7R-driven cases), ABL and SRC family tyrosine kinase (for LCK-activated cases), MEK or PI3K-mTOR inhibitors. MYC-targeting agents, DNA demethylating agents, histone deacetylase inhibitors, splicing modulators, or drugs exploring T-ALL metabolic vulnerabilities, are other examples for potential pharmacological intervention. Immunotherapies, particularly CAR T-cell products targeting CD7 and other markers, but also biologics (e.g. targeting CD38), are under development and increasing interest. These agents should be rationally integrated into precision medicine combination therapies informed by genetic, epigenetic, and posttranscriptional insights that will be essential to refine risk stratification and minimize the risk of resistance. Novel strategies leveraging artificial intelligence and machine learning could accelerate discovery and optimize treatment frameworks.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"66 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840037","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}
引用次数: 0
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