Epigenetic reactivation of a tumor suppressor program in leukemia

Tumor suppressor genes (TSGs) impart a cellular fitness in human cancers, including acute myeloid leukemia (AML). In contrast to loss-of-function mutations, the siliencing of TSGs without direct mutations further complicates the clinical management of AML. Here, we conducted genome-scale phenotypic CRISPR-Cas9 screens to uncover genes that suppress leukemia differentiation. These screens revealed ZBTB7A as a transcriptional repressor that is downregulated in leukemia stem cells (LSCs) and associated with poor clinical outcome. Mechanistically, we found that the mRNA decay factor ZFP36L2 binds to its 3'-untranslated region (UTR) of ZBTB7A to induct its transcript degradation. Furthermore, the loss of ZBTB7A enhances the transcriptional activation of TNF signaling, resulting in an aberrant inflammatory state that drives leukemia 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 ZBTB7A's tumor suppressor fuction. Pharmacologic inhibition of KDM4 elevated ZBTB7A levels, triggered terminal AML differentiation, an dexhibited broad anti-leukemic effects. Finally, targeting of KDM4 in vivo extended survival of leukemic mice while preserving normal hematopoiesis. Together, our work elucidates key regulatory pathways underlying ZBTB7A's tumor suppressor role and highlights an epigenetic therapy as a potential strategy to restore its function in cancer.