{"title":"CD69 blockade restores the bone marrow niche and delays leukemogenesis in a mouse model of <i>Nras</i> <sup>G12D</sup>-driven chronic myelomonocytic leukemia.","authors":"Yuchen Li, Xu Jiang, Yinfeng Gu, Xianfeng Zha, Jie Wu, Xiuli Wu, Chunli Qi, Shaohua Chen, Yangqiu Li, Zhenyi Jin, Chengxiang Xia, Ling Xu","doi":"10.1080/15384047.2026.2692184","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>A subset of patients with chronic myelomonocytic leukemia (CMML) carries <i>NRAS</i> mutations, which are associated with shorter overall survival and an increased risk of transformation to acute myeloid leukemia. However, the effects of <i>NRAS</i> mutations on the bone marrow microenvironment (BME) remain unclear.</p><p><strong>Methods: </strong>We used a CMML mouse model driven by a single <i>Nras</i> <sup>G12D</sup> allele mutation to investigate alterations in the BME and the potential role of CD69 in immune suppression. <i>Nras</i> <sup>G12D</sup>-mutated CMML mice were treated with an anti-CD69 monoclonal antibody. Flow cytometry, hematoxylin-eosin staining, and RNA sequencing were performed to evaluate treatment-related changes.</p><p><strong>Results: </strong><i>Nras</i> <sup>G12D</sup>-mutated CMML mice showed increased infiltration of regulatory T (Treg) cells and CD69<sup>+</sup> T cells in the BME, whereas CD69 expression on peripheral blood T cells remained lower than that on bone marrow T cells. Anti-CD69 monoclonal antibody treatment was associated with reduced generation of granulocyte-macrophage progenitor cells, prolonged survival, and decreased Treg accumulation in the BME.</p><p><strong>Conclusion: </strong>Our findings suggest that CD69 may serve as a biomarker of BME immunological dysfunction in CMML.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"27 1","pages":"2692184"},"PeriodicalIF":5.7000,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13290085/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Biology & Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/15384047.2026.2692184","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/6/22 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: A subset of patients with chronic myelomonocytic leukemia (CMML) carries NRAS mutations, which are associated with shorter overall survival and an increased risk of transformation to acute myeloid leukemia. However, the effects of NRAS mutations on the bone marrow microenvironment (BME) remain unclear.
Methods: We used a CMML mouse model driven by a single NrasG12D allele mutation to investigate alterations in the BME and the potential role of CD69 in immune suppression. NrasG12D-mutated CMML mice were treated with an anti-CD69 monoclonal antibody. Flow cytometry, hematoxylin-eosin staining, and RNA sequencing were performed to evaluate treatment-related changes.
Results: NrasG12D-mutated CMML mice showed increased infiltration of regulatory T (Treg) cells and CD69+ T cells in the BME, whereas CD69 expression on peripheral blood T cells remained lower than that on bone marrow T cells. Anti-CD69 monoclonal antibody treatment was associated with reduced generation of granulocyte-macrophage progenitor cells, prolonged survival, and decreased Treg accumulation in the BME.
Conclusion: Our findings suggest that CD69 may serve as a biomarker of BME immunological dysfunction in CMML.
期刊介绍：
Cancer, the second leading cause of death, is a heterogenous group of over 100 diseases. Cancer is characterized by disordered and deregulated cellular and stromal proliferation accompanied by reduced cell death with the ability to survive under stresses of nutrient and growth factor deprivation, hypoxia, and loss of cell-to-cell contacts. At the molecular level, cancer is a genetic disease that develops due to the accumulation of mutations over time in somatic cells. The phenotype includes genomic instability and chromosomal aneuploidy that allows for acceleration of genetic change. Malignant transformation and tumor progression of any cell requires immortalization, loss of checkpoint control, deregulation of growth, and survival. A tremendous amount has been learned about the numerous cellular and molecular genetic changes and the host-tumor interactions that accompany tumor development and progression. It is the goal of the field of Molecular Oncology to use this knowledge to understand cancer pathogenesis and drug action, as well as to develop more effective diagnostic and therapeutic strategies for cancer. This includes preventative strategies as well as approaches to treat metastases. With the availability of the human genome sequence and genomic and proteomic approaches, a wealth of tools and resources are generating even more information. The challenge will be to make biological sense out of the information, to develop appropriate models and hypotheses and to translate information for the clinicians and the benefit of their patients. Cancer Biology & Therapy aims to publish original research on the molecular basis of cancer, including articles with translational relevance to diagnosis or therapy. We will include timely reviews covering the broad scope of the journal. The journal will also publish op-ed pieces and meeting reports of interest. The goal is to foster communication and rapid exchange of information through timely publication of important results using traditional as well as electronic formats. The journal and the outstanding Editorial Board will strive to maintain the highest standards for excellence in all activities to generate a valuable resource.
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