HOXA9 is a sequence-specific transcription factor that acts as a master regulator of hematopoietic development and a proto-oncogene in acute leukemias 1. In normal hematopoiesis, HOXA9 is sufficient to convert hemogenic endothelium into functional hematopoietic stem and progenitor cells capable of multi-lineage engraftment 2. However, HOXA9 is aberrantly expressed in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), where it is both necessary and sufficient for leukemic transformation and correlates with poor prognosis 1. Mechanistically, HOXA9 maintains leukemia through multiple pathways: it forms repressive chr7 complexes with SAFB and NuRD complexes to block myeloid differentiation genes 3, and its aberrant activation through NUP98-HOXA9 fusion proteins drives phase separation-mediated super-enhancer formation at proto-oncogenes 4. Additionally, HOXA9 translation is enhanced through ac4C RNA modification by NAT10, which sustains leukemic stem cell self-renewal via serine metabolism reprogramming 5. Therapeutic strategies targeting HOXA9-driven leukemia include DOT1L, MENIN, and RBM39 inhibitors that disrupt HOXA9 expression or function 671.