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Patients with leukemic cutaneous T-cell lymphoma have a poor prognosis because of the development of drug resistance and severe bacterial infections. In this study, we show that most patients with leukemic cutaneous T-cell lymphoma harbor multiple genetically distinct subclones that express an identical clonal antigen receptor but display distinct phenotypes and functional properties. These coexisting malignant subclones exhibit differences in tissue homing, metabolism, and cytokine expression and respond differently to extrinsic factors like Staphylococcus aureus and cancer drugs. Indeed, although S. aureus toxins selectively enhance activation and proliferation of certain subclones, these responsive subclones are also the most intrinsically sensitive to cancer drugs when the stimuli are removed. Consequently, although the divergent evolution of malignant subclones drives aggressiveness, adaptability, and drug resistance by removing extrinsic stimuli and mapping malignant subclones, we can expose inherent vulnerabilities that can be exploited in the treatment of these cancers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>Cancer cells have inherent disparity in hallmark traits, such as aggressiveness and intrinsic drug resistance. We show that segregation of hallmark traits on different coexisting subclones is common and augments adaptability, aggressiveness, and drug resistance of the overall cancer population. Importantly, this segregation exposes vulnerabilities that can be exploited in individualized therapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-24-1856","type":"journal-article","created":{"date-parts":[[2025,6,14]],"date-time":"2025-06-14T14:08:27Z","timestamp":1749910107000},"page":"2036-2053","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Divergent Evolution of Malignant Subclones Maintains a Balance between Induced Aggressiveness and Intrinsic Drug Resistance in T-cell Cancer"],"prefix":"10.1158","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7180-6384","authenticated-orcid":false,"given":"Terkild B.","family":"Buus","sequence":"first","affiliation":[{"name":"1Department of Immunology and Microbiology, LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3710-5143","authenticated-orcid":false,"given":"Chella Krishna","family":"Vadivel","sequence":"additional","affiliation":[{"name":"1Department of Immunology and Microbiology, LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8877-3486","authenticated-orcid":false,"given":"Maria","family":"Gluud","sequence":"additional","affiliation":[{"name":"1Department of Immunology and Microbiology, LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7526-7883","authenticated-orcid":false,"given":"Martin R.J.","family":"Namini","sequence":"additional","affiliation":[{"name":"1Department of Immunology and Microbiology, LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9138-602X","authenticated-orcid":false,"given":"Ziao","family":"Zeng","sequence":"additional","affiliation":[{"name":"1Department of Immunology and Microbiology, LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2481-035X","authenticated-orcid":false,"given":"Signe","family":"Hedebo","sequence":"additional","affiliation":[{"name":"2Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2694-0848","authenticated-orcid":false,"given":"Menghong","family":"Yin","sequence":"additional","affiliation":[{"name":"3Translational Skin Cancer Research, German 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