Retinal determination network reactivation drives chemoresistance and blocks myeloid differentiation in acute myeloid leukemia

Acute myeloid leukemia (AML) is a heterogeneous malignancy driven by abnormal transcriptional programs that block myeloid differentiation and sustain self-renewal. Despite treatment advances over the last 30 years, refractory responses remain common, underscoring the need for new therapies. Here, we reveal the reactivation of retinal determination gene network (RDGN) members SIX1 and EYA1 in MOZ- and MLL-rearranged AMLs. We demonstrate that the SIX1-EYA1 complex enhances HOXA9-driven transformation, reinforcing differentiation blocks and maintaining leukemic blast morphology. RDGN members are expressed in both mouse and human AML cells, within discrete subpopulations that inversely correlate with MEIS1/HOXA9 expression. We demonstrate that the expression of RDGN members contributes to chemoresistance via enhanced DNA damage repair. Genetic ablation of SIX1 and pharmacological disruption of the SIX1/EYA1 interaction impair AML maintenance and resensitize cells to DNA-damaging therapies. These findings establish RDGN as a promising therapeutic target in AML and potentially in solid tumors marked by SIX1/RDGN re-expression.