Abstract 6712: Epigenetic reactivation of a tumor suppressor program in leukemia

Tumor suppressor genes (TSGs) impart a cellular fitness in human cancers, including acute myeloid leukaemia (AML). In contrast to genetic alterations, silencing of TSGs without direct mutations lacks genomic scars, thereby complicating the clinical management of AML. Here we conducted genome-scale phenotypic CRISPR/Cas9 screens to uncover genes that suppress leukaemia differentiation. We identified ZBTB7A, a transcriptional repressor that is downregulated in leukaemia stem cells (LSCs) and associated with poor survival outcomes in AML patients. Our results show that the mRNA decay factor ZFP36L2 binds to the 3’-untranslated region (UTR) of ZBTB7A to induce its mRNA degradation. Mechanistically, the loss of ZBTB7A promotes a dysregulated inflammatory state that drives leukaemia progression. To explore the translational potential, we coupled in situ Flow-FISH readout with CRISPR-based screening which identified KDM4 as a therapeutic vulnerability to restore the tumor suppressive function of ZBTB7A. Pharmacologic inhibition of KDM4 elevated ZBTB7A levels, induced terminal leukaemia differentiation, and broad anti-leukemic efficacy across AML subtypes. Inhibition of KDM4 in vivo prolonged survival of leukemic mice while sparing normal haematopoiesis. Together, our findings reveal regulatory circuits underlying the tumor suppressive role of ZBTB7A and highlights an epigenetic therapy to restore its function in myeloid malignancies. Citation Format: Eric Wang, Cuijuan Han, Alexander Calderon, Iannis Aifantis, Aristotelis Tsirigos, Abimbo Lawal, Sakthi H. Rajendran, Sadik Karma, Hussein A. Abbas, Mhd Y. Yassouf, Zhiping Zhang, Pedro Miura. Epigenetic reactivation of a tumor suppressor program in leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6712.