{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T19:08:21Z","timestamp":1776884901303,"version":"3.51.2"},"reference-count":41,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T00:00:00Z","timestamp":1750982400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82204352"],"award-info":[{"award-number":["82204352"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The clinical guideline classifies T\u2010LBL and T\u2010ALL 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Results<\/jats:title><jats:p>We established the NCH\u2010TALL\u2010LBL cohort, which includes flow cytometry data and somatic mutation data from our center. Additionally, we collected T\u2010LBL samples and implemented single\u2010cell RNA sequencing and single\u2010cell T\u2010cell receptor sequencing. Combining the single\u2010cell RNA sequencing data of T\u2010ALL, expression array data, flow cytometry data, we discovered that malignant T cells in T\u2010LBL are predominantly in the DN\u2010 and DP\u2010stage blocking modes (DP cells dominate). This block mode in T\u2010LBL 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\u2010LBL.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>From the perspective of differentiation blockage, T\u2010LBL and T\u2010ALL represent different stages of the same disease, and the stage block bias of T\u2010cell contributes to their heterogeneity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Malignant T cells in T\u2010LBL are primarily blocked in the DN and DP stages, which contributes to the immunosuppressive TME and mediastinum preference of T\u2010LBL.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The active transcription factor E2F2 in the DP and DN stages upregulates UHRF1 expression, leading to the hypermethylation of tumor suppressor genes in T\u2010LBL.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Demethylation therapy targeting the hypermethylation of tumor suppressor genes mediated by UHRF1 effectively inhibits tumor proliferation in T\u2010LBL.<\/jats:p><\/jats:list-item><\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.70380","type":"journal-article","created":{"date-parts":[[2025,6,28]],"date-time":"2025-06-28T00:54:53Z","timestamp":1751072093000},"source":"Crossref","is-referenced-by-count":2,"title":["T\u2010cell differentiation stage block bias confers hypermethylation and mediastinal preference in T\u2010cell lymphoblastic lymphoma"],"prefix":"10.1002","volume":"15","author":[{"given":"Jiali","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Hematology and Oncology Children's Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Qian","sequence":"additional","affiliation":[{"name":"Department of 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