CBFβ-SMMHC requires RUNX1 for leukemia development. (A) Under normal conditions, hematopoietic stem and progenitor cells (HSPC) are converted to LICs by the action of the inv(16)-derived fusion oncoprotein, CBFβ-SMMHC, in combination with an activating mutation in a signaling molecule, such as NRAS, KRAS, or FLT3. The existing paradigm has been that CBFβ-SMMHC drives leukemia development by acting as a dominant negative which sequesters RUNX1, preventing it from promoting normal myeloid development. Zhen et al demonstrate that loss of RUNX1 prevents leukemia development in mice by preventing the development and maintenance of AMPs, a type of LIC specific to inv(16). (B) In AMP cells, RUNX1 recruits CBFβ-SMMHC to chromatin, where RUNX1:CBFβ-SMMHC predominantly activate cell cycle gene expression while simultaneously repressing a smaller number of genes that promote differentiation.