Researchers from The Jackson Laboratory and collaborators reported an epigenetic approach that restores a tumor suppressor in acute myeloid leukemia by inhibiting KDM4 enzymes. The work, published in Science Translational Medicine, centers on reactivating ZBTB7A, a gene silenced in AML through chromatin regulation rather than mutation. Using a tool combining fluorescence in situ hybridization, flow cytometry, and CRISPR gene editing (FISHnCRISP), the team mapped gene activity in leukemia cells to identify ZBTB7A as the target. In mice, blocking KDM4 restored ZBTB7A expression and reduced leukemia burden while largely preserving normal blood formation. The strategy shifts the therapeutic frame away from solely killing leukemia cells toward restoring silenced regulatory pathways, offering a blueprint for targeting other epigenetically repressed tumor suppressors.