Inactivation of tumor suppressor genes (TSGs) impart a cellular fitness in cancers, including acute myeloid leukemia (AML). The silencing of TSGs without direct mutations presents challenges in cancer therapy but also presents a therapeutic opportunity to restore their function. In this study, we identified the transcriptional repressor ZBTB7A as a TSG that is downregulated in AML and associated with poor survival outcomes. Loss of ZBTB7A amplifies TNF signaling, driving a dysfunctional inflammatory state that accelerates leukemia progression. Mechanistically, the mRNA decay factor ZFP36L2 binds to the 3' untranslated region (3'UTR) of ZBTB7A, promoting its transcript degradation. To uncover therapeutic strategies, we developed a CRISPR-based screening approach coupled with in situ FISH-Flow, pinpointing KDM4 as a vulnerability to restore ZBTB7A function. Pharmacologic inhibition of KDM4 enhanced ZBTB7A expression, promoted terminal differentiation of leukemic cells, and demonstrated broad anti-leukemic activity across AML subtypes while preserving normal hematopoiesis. These findings reveal critical regulatory mechanisms of ZBTB7A and support epigenetic therapy as a promising strategy to reactivate its tumor suppressor function in hematologic cancers.

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2025
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