Researchers at The Jackson Laboratory (JAX) and collaborators identified an epigenetic strategy to restore the tumor suppressor ZBTB7A in acute myeloid leukemia (AML) models. Their mouse data, published in Science Translational Medicine, show that inhibiting KDM4 can reactivate ZBTB7A expression and reduce leukemia burden. The team used a mapping tool combining fluorescence in situ hybridization and flow cytometry with CRISPR gene editing (FISHnCRISP) to pinpoint ZBTB7A silencing. Mechanistically, the authors link a longer ZBTB7A regulatory tail to ZFP36L2-mediated repression and connect the suppression to KDM4’s DNA packaging effects. Importantly, blocking KDM4 improved leukemia outcomes while largely preserving normal blood formation in the study’s experiments. The work also adds a generalizable approach for identifying gene-silencing mechanisms that are missed by mutation-first sequencing.