{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T05:48:20Z","timestamp":1779342500777,"version":"3.51.4"},"reference-count":16,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T00:00:00Z","timestamp":1755216000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Chronic Lymphocytic Leukemia (CLL) is characterized by clinical and biological heterogeneity, with a subset of patients progressing to Richter Transformation (RT), an aggressive lymphoma. This study explores MYC target gene activation across various CLL stages and disease subgroups using bulk RNAseq and single-cell RNAseq data. Our findings reveal increased MYC activation in unmutated IGHV CLLs, trisomy 12 cases, and RT stages. In RT, MYC activation is independent of B-cell receptor signaling, correlating instead with cell cycling and TLR9 interactions, indicating alternative survival mechanisms. High MYC activation correlates with shorter time to first treatment and enhances tumor microenvironment interactions, particularly with myeloid cells. These results underscore MYC\u2019s significant role in CLL progression and RT, supporting MYC\u2019s potential as a target for stratifying CLL patients and developing therapeutic strategies.<\/jats:p>","DOI":"10.3389\/fphar.2025.1642458","type":"journal-article","created":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T05:29:07Z","timestamp":1755235747000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["MYC target gene activation in chronic lymphocytic leukemia and richter transformation: links to aggressiveness and tumor microenvironment interactions"],"prefix":"10.3389","volume":"16","author":[{"given":"M.","family":"Tsagiopoulou","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S.","family":"Rashmi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"Chatziaslani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"I.","family":"Gut","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"594841","DOI":"10.3389\/fimmu.2020.594841","article-title":"Microenvironment remodeling and subsequent clinical implications in diffuse large B-Cell histologic variant of richter syndrome","volume":"11","author":"Auge","year":"2020","journal-title":"Front. Immunol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/j.tcb.2022.07.006","article-title":"MYC: a complex problem","volume":"33","author":"Das","year":"2023","journal-title":"Trends Cell Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"2205","DOI":"10.3324\/haematol.2019.236000","article-title":"Chronic lymphocytic leukemia: from molecular pathogenesis to novel therapeutic strategies","volume":"105","author":"Delgado","year":"2020","journal-title":"Haematologica"},{"key":"B4","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1038\/s41571-021-00549-2","article-title":"The MYC oncogene - the grand orchestrator of cancer growth and immune evasion","volume":"19","author":"Dhanasekaran","year":"2022","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1182\/blood-2010-05-284984","article-title":"The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia","volume":"117","author":"Herishanu","year":"2011","journal-title":"Blood"},{"key":"B6","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1111\/j.1365-2141.2008.07152.x","article-title":"MYC translocation in chronic lymphocytic leukaemia is associated with increased prolymphocytes and a poor prognosis","volume":"142","author":"Huh","year":"2008","journal-title":"Br. J. Haematol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"3064","DOI":"10.1182\/blood.2020005964","article-title":"TLR9 expression in chronic lymphocytic leukemia identifies a promigratory subpopulation and novel therapeutic target","volume":"137","author":"Kennedy","year":"2021","journal-title":"Blood"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1664","DOI":"10.1038\/s41588-022-01140-w","article-title":"Molecular map of chronic lymphocytic leukemia and its impact on outcome","volume":"54","author":"Knisbacher","year":"2022","journal-title":"Nat. Genet."},{"key":"B9","doi-asserted-by":"publisher","first-page":"3619","DOI":"10.1182\/blood.2022017839","article-title":"Inhibition of MYC translation through targeting of the newly identified PHB-eIF4F complex as a therapeutic strategy in CLL","volume":"7","author":"Largeot","year":"2023","journal-title":"Blood Adv."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1662","DOI":"10.1038\/s41591-022-01927-8","article-title":"Detection of early seeding of richter transformation in chronic lymphocytic leukemia","volume":"28","author":"Nadeu","year":"2022","journal-title":"Nat. Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"18261","DOI":"10.1073\/pnas.0606108103","article-title":"NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth","volume":"103","author":"Palomero","year":"2006","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B12","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1038\/s41467-019-14081-6","article-title":"Chromatin mapping and single-cell immune profiling define the temporal dynamics of ibrutinib response in CLL","volume":"11","author":"Rendeiro","year":"2020","journal-title":"Nat. Commun."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1396","DOI":"10.1056\/NEJMoa1801445","article-title":"Genetics and pathogenesis of diffuse large B-Cell lymphoma","volume":"378","author":"Schmitz","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e26837","DOI":"10.1371\/journal.pone.0026837","article-title":"Deep sequencing of MYC DNA-Binding sites in burkitt lymphoma","volume":"6","author":"Seitz","year":"2011","journal-title":"PLoS One"},{"key":"B15","first-page":"348","article-title":"Richter transformation of chronic lymphocytic leukemia in the era of novel agents","volume":"18","author":"Wang","year":"2020","journal-title":"Clin. Adv. Hematol. Oncol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1182\/blood-2015-07-660969","article-title":"Engagement of the B-cell receptor of chronic lymphocytic leukemia cells drives global and MYC-Specific mRNA translation","volume":"127","author":"Yeomans","year":"2016","journal-title":"Blood"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1642458\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T05:29:08Z","timestamp":1755235748000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1642458\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,15]]},"references-count":16,"alternative-id":["10.3389\/fphar.2025.1642458"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1642458","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,15]]},"article-number":"1642458"}}