Through biochemical and functional characterization of RASSF2 in leukemia models, we establish that a SARAH domain-dependent interaction with Hippo kinases MST1 and MST2 is absolutely essential for stabilization of RASSF2 protein and for its tumor-suppressive function against RUNX1-ETO-mediated leukemogenesis. The gene discussed is RUNX1; the disease is leukemia.