Model for T/myeloid MPAL induced by ETV6-NCOA2. Expression of the EVT6-NCOA2 fusion oncoprotein in HSPCs leads to formation of an aberrant transcriptional complex via binding to wild-type ETV6 and the transcriptional coactivator p300. This causes de-repression of ETV6 target genes, including NOTCH targets (HES1 and DLL4) and early lymphoid genes (IL7RA and GATA3) that promote lymphoid commitment while maintaining the expression of myeloid regulatory genes (CSF1 and MEF2C) that block further lymphoid differentiation. This causes differentiation arrest of multipotent T/myeloid progenitors, which accumulate further mutations, such as activating NOTCH1 mutations, that result in overt T/myeloid MPAL.