Gain-of-function somatic mutations of SET binding protein 1 (SETBP1) result in the accumulation of SETBP protein and are detected in 17% of secondary acute myeloid leukemia (AML) patients.1 In fact, high expression of SETBP1 also drives adverse outcomes in human AML. However, the roles of SETBP1 during developmental hematopoiesis and AML progression are still not fully understood.