The overall prognosis of acute myeloid leukemia (AML) remains dismal, largely due to the inability of current therapies to kill leukemia stem cells (LSCs) with intrinsic resistance. Loss of the stress sensor GADD45A is implicated in poor clinical outcomes but its role in LSCs and AML pathogenesis is unknown. Here we define GADD45A as a key downstream target of LGR4 oncogenic signaling and discover a regulatory role for GADD45A loss in promoting leukemia-initiating activity and …