HOXA9 forms a repressive complex with nuclear matrix-associated protein SAFB to maintain acute myeloid leukemia

Abstract

AbstractHOXA9is commonly upregulated in acute myeloid leukemia (AML), where it confers poor prognosis. Characterising the protein interactome of endogenous HOXA9 in human AML, we identified a chromatin complex of HOXA9 with the nuclear matrix attachment protein-SAFB.SAFBperturbation phenocopiedHOXA9knockout to decrease AML proliferation, increase differentiation and apoptosisin vitroand prolonged survivalin vivo. Integrated genomic, transcriptomic and proteomic analyses further demonstrated that the HOXA9-SAFB-chromatin complex associates with NuRD and HP1γ to repress the expression of factors associated with differentiation and apoptosis, includingNOTCH, CEBPδ,S100A8, andCDKN1A. Chemical or genetic perturbation of NuRD and HP1γ catalytic activity also triggered differentiation, apoptosis and the induction of these tumor-suppressive genes. Importantly, this mechanism is operative in other HOXA9-dependent AML genotypes. This mechanistic insight demonstrates activeHOXA9-dependent differentiation block as a potent mechanism of disease maintenance in AML, that may be amenable to therapeutic intervention via therapies targeting the HOXA9/SAFB interface and/or NuRD and HP1γ activity.Key Points-Identification of the endogenous human HOXA9 protein interactome in AML-HOXA9 forms a repressive complex with S/MAR binding protein (SAFB) that is critical for the maintenance of AML by facilitating proliferation and preventing differentiation and cell death.-The HOXA9/SAFB (H9SB) complex represses gene expression via recruitment of NuRD and HP1γ.