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The detection of silenced TSGs without direct mutations presents challenges in designing targeted cancer treatments, yet it also opens a therapeutic opportunity to restore their function. In this study, we identified the transcriptional repressor\n                    <jats:italic toggle=\"yes\">ZBTB7A<\/jats:italic>\n                    as a TSG that is down-regulated in samples from patients with AML and is associated with poor survival outcomes. Loss of ZBTB7A amplifies TNF signaling, driving a dysfunctional inflammatory state that accelerates AML progression in vivo. Mechanistically, the mRNA decay factor ZFP36L2 binds to the 3\u2032 untranslated region (3\u2032UTR) of\n                    <jats:italic toggle=\"yes\">ZBTB7A<\/jats:italic>\n                    , promoting its transcript degradation in human AML cells. To identify therapeutic targets, we developed a CRISPR-based screening approach coupled with fluorescence in situ hybridization and flow cytometry (FISH-Flow), pinpointing the KDM4 family of histone demethylases as a vulnerability to restore ZBTB7A function. Pharmacologic inhibition of KDM4 up-regulated ZBTB7A expression, promoted terminal differentiation in patient-derived xenograft models, and demonstrated broad antileukemic efficacy across AML subtypes as well as preserved normal hematopoiesis. These findings reveal regulatory mechanisms of ZBTB7A and support epigenetic therapy as a promising strategy to reactivate its tumor suppressor function in hematologic cancers.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.ady2936","type":"journal-article","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T18:58:16Z","timestamp":1772045896000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["Epigenetic reactivation of the tumor suppressor ZBTB7A by KDM4 inhibition in human acute myeloid leukemia"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7134-6282","authenticated-orcid":true,"given":"Alexander","family":"Arnuk","sequence":"first","affiliation":[{"name":"Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, 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