{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T11:28:33Z","timestamp":1789730913963,"version":"4.0.1"},"reference-count":41,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T00:00:00Z","timestamp":1775606400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T00:00:00Z","timestamp":1775606400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100010226","name":"Department of Education of Guangdong Province","doi-asserted-by":"publisher","award":["2024KTSCX169"],"award-info":[{"award-number":["2024KTSCX169"]}],"id":[{"id":"10.13039\/501100010226","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Acquired resistance represents a fundamental obstacle limiting the long\u2010term efficacy of cancer chemotherapy. In T\u2010cell acute lymphoblastic leukemia (T\u2010ALL), the nucleoside analog prodrug nelarabine is a critical salvage therapy for relapsed\/refractory (R\/R) patients; however, resistance is common and rapid, worsening prognosis. The molecular mechanisms underlying this process remain largely to be elucidated. Here, we identify the oncogene MYC as a key functional mediator driving nelarabine resistance. Through unbiased transcriptomic profiling and functional validation, we demonstrate that nelarabine\u2010resistant T\u2010ALL cells develop a profound addiction to a hyperactive MYC transcriptional program. Critically, MYC knockdown restores nelarabine sensitivity, causally linking MYC to the resistant phenotype. While this discovery reveals a therapeutic vulnerability, MYC itself is considered an \u2018undruggable\u2019 protein, making direct inhibition a formidable challenge. We therefore pursued an indirect strategy, employing BET family protein degraders to dismantle the upstream epigenetic machinery essential for MYC transcription. Consistent with a MYC\u2010driven mechanism, treatment with ARV\u2010771 and ARV\u2010825 induced potent degradation of BET proteins, suppressed MYC transcription, and profoundly impaired the viability and proliferation of nelarabine\u2010resistant cells. Importantly, this strategy showed strong therapeutic efficacy in an in\u00a0vivo model of nelarabine\u2010resistant T\u2010ALL, significantly reducing leukemia burden and extending survival. Our work establishes the first mechanistic link between nelarabine resistance and MYC dependency, providing a compelling preclinical rationale and therapeutic strategy to overcome this challenge. Collectively, this study offers a paradigm for reversing chemotherapy resistance by exploiting acquired transcriptional addictions.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Trial Registration:<\/jats:bold>\n                    Registry and the Registration No. of the study\/trial. Yes, approved number: IRB Approval No.: Med\u2010Ethics [2026] IIT No. (19)\n                  <\/jats:p>","DOI":"10.1111\/cas.70382","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T08:16:56Z","timestamp":1775636216000},"page":"1608-1622","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>MYC<\/scp>\n                    Addiction as a Targetable Vulnerability in Nelarabine\u2010Resistant T\u2010Cell Acute Lymphoblastic Leukemia"],"prefix":"10.1111","volume":"117","author":[{"given":"Jingjing","family":"Gao","sequence":"first","affiliation":[{"name":"Center for Drug Research and Development Guangdong Pharmaceutical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunxu","family":"Lin","sequence":"additional","affiliation":[{"name":"Pharmacy Department The Eighth People's Hospital of Longgang District  Shenzhen 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