Jiali Wang, Bo Qian, Xiaowen Yu, Yidan Zhang, Chunlei Zhou, Tingting Yang, Le Xia, Gang Zhang, Yi-Xuan Zhang, Yaping Wang, Yongjun Fang
{"title":"t细胞分化期阻滞偏倚导致t细胞淋巴母细胞淋巴瘤的超甲基化和纵隔偏好","authors":"Jiali Wang, Bo Qian, Xiaowen Yu, Yidan Zhang, Chunlei Zhou, Tingting Yang, Le Xia, Gang Zhang, Yi-Xuan Zhang, Yaping Wang, Yongjun Fang","doi":"10.1002/ctm2.70380","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>The clinical guideline classifies T-LBL and T-ALL jointly, differentiating them merely by the bone marrow blast cell proportion. However, their distinct clinical manifestations, genetic profiles, and specific pathogenic requirements have prompted us to reevaluate the differences between them.</p>\n </section>\n \n <section>\n \n <h3> Methods and Results</h3>\n \n <p>We established the NCH-TALL-LBL cohort, which includes flow cytometry data and somatic mutation data from our center. Additionally, we collected T-LBL samples and implemented single-cell RNA sequencing and single-cell T-cell receptor sequencing. Combining the single-cell RNA sequencing data of T-ALL, expression array data, flow cytometry data, we discovered that malignant T cells in T-LBL are predominantly in the DN- and DP-stage blocking modes (DP cells dominate). This block mode in T-LBL generates signals that drive the development of an immunosuppressive microenvironment and the mediastinum preference. Additionally, E2F2, an active transcription factor in the DP and DN stages, upregulates the expression of UHRF1, resulting in hypermethylation of tumor suppressor genes. Findings from in vivo and in vitro research clearly show that demethylation therapy targeting this mechanism effectively inhibits tumor proliferation in T-LBL.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>From the perspective of differentiation blockage, T-LBL and T-ALL represent different stages of the same disease, and the stage block bias of T-cell contributes to their heterogeneity.</p>\n </section>\n \n <section>\n \n <h3> Key points</h3>\n \n <div>\n <ul>\n \n <li>Malignant T cells in T-LBL are primarily blocked in the DN and DP stages, which contributes to the immunosuppressive TME and mediastinum preference of T-LBL.</li>\n \n <li>The active transcription factor E2F2 in the DP and DN stages upregulates UHRF1 expression, leading to the hypermethylation of tumor suppressor genes in T-LBL.</li>\n \n <li>Demethylation therapy targeting the hypermethylation of tumor suppressor genes mediated by UHRF1 effectively inhibits tumor proliferation in T-LBL.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 7","pages":""},"PeriodicalIF":6.8000,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70380","citationCount":"0","resultStr":"{\"title\":\"T-cell differentiation stage block bias confers hypermethylation and mediastinal preference in T-cell lymphoblastic lymphoma\",\"authors\":\"Jiali Wang, Bo Qian, Xiaowen Yu, Yidan Zhang, Chunlei Zhou, Tingting Yang, Le Xia, Gang Zhang, Yi-Xuan Zhang, Yaping Wang, Yongjun Fang\",\"doi\":\"10.1002/ctm2.70380\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>The clinical guideline classifies T-LBL and T-ALL jointly, differentiating them merely by the bone marrow blast cell proportion. However, their distinct clinical manifestations, genetic profiles, and specific pathogenic requirements have prompted us to reevaluate the differences between them.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods and Results</h3>\\n \\n <p>We established the NCH-TALL-LBL cohort, which includes flow cytometry data and somatic mutation data from our center. Additionally, we collected T-LBL samples and implemented single-cell RNA sequencing and single-cell T-cell receptor sequencing. Combining the single-cell RNA sequencing data of T-ALL, expression array data, flow cytometry data, we discovered that malignant T cells in T-LBL are predominantly in the DN- and DP-stage blocking modes (DP cells dominate). This block mode in T-LBL generates signals that drive the development of an immunosuppressive microenvironment and the mediastinum preference. 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T-cell differentiation stage block bias confers hypermethylation and mediastinal preference in T-cell lymphoblastic lymphoma
Background
The clinical guideline classifies T-LBL and T-ALL jointly, differentiating them merely by the bone marrow blast cell proportion. However, their distinct clinical manifestations, genetic profiles, and specific pathogenic requirements have prompted us to reevaluate the differences between them.
Methods and Results
We established the NCH-TALL-LBL cohort, which includes flow cytometry data and somatic mutation data from our center. Additionally, we collected T-LBL samples and implemented single-cell RNA sequencing and single-cell T-cell receptor sequencing. Combining the single-cell RNA sequencing data of T-ALL, expression array data, flow cytometry data, we discovered that malignant T cells in T-LBL are predominantly in the DN- and DP-stage blocking modes (DP cells dominate). This block mode in T-LBL generates signals that drive the development of an immunosuppressive microenvironment and the mediastinum preference. Additionally, E2F2, an active transcription factor in the DP and DN stages, upregulates the expression of UHRF1, resulting in hypermethylation of tumor suppressor genes. Findings from in vivo and in vitro research clearly show that demethylation therapy targeting this mechanism effectively inhibits tumor proliferation in T-LBL.
Conclusion
From the perspective of differentiation blockage, T-LBL and T-ALL represent different stages of the same disease, and the stage block bias of T-cell contributes to their heterogeneity.
Key points
Malignant T cells in T-LBL are primarily blocked in the DN and DP stages, which contributes to the immunosuppressive TME and mediastinum preference of T-LBL.
The active transcription factor E2F2 in the DP and DN stages upregulates UHRF1 expression, leading to the hypermethylation of tumor suppressor genes in T-LBL.
Demethylation therapy targeting the hypermethylation of tumor suppressor genes mediated by UHRF1 effectively inhibits tumor proliferation in T-LBL.
期刊介绍：
Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.
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