Loss-of-function mutations in RUNX1 (mutRUNX1) impair gene regulation of ribosomal biogenesis and protein translation, c-MYC, as well as myeloid differentiation regulators (left, lineage-specific transcription factor [LSTF]). Pharmacologic inhibition of protein synthesis using homoharringtonine or omacetaxine (HTT/OM)-induced myeloid differentiation despite also reducing RUNX1 and PU.1, as well as lowering BCL2 and MCL1 levels, which renders RUNX1mut AML cells more sensitive to apoptotic elimination following venetoclax or BET inhibition (OTX015) (VEN/OTX) (right). Figure created with BioRender.com.