Abstract
Mutations in SET binding protein 1 ( SETBP1 ) are associated with an adverse prognosis in myeloid malignancies. These mutations stabilize SETBP1 protein, driving increased expression of a progenitor-associated gene expression program through incompletely described mechanisms. A proteomic screen revealed interactions between SETBP1 and members of the MYST acetyltransferase complexes, including the catalytic subunits-KAT6A and KAT7. Mutant SETBP1 increases the localization of MYST complexes at known SETBP1 target genes, including the Hoxa cluster, where it drives increased histone acetylation and gene expression. Treatment of SETBP1 (D868N) -expressing myeloid progenitors with MYST inhibitors reduced target gene expression. To establish the efficacy of MYST inhibition in vivo , we treated mice harboring a syngeneic SETBP1 -mutant leukemia with the clinical-grade MYST inhibitor-PF-9363. This resulted in complete hematologic control and increased survival. MYST inhibition was also highly effective against a SETBP1 -mutant PDX model. These studies identify MYST acetyltransferases as promising therapeutic targets in SETBP1 -mutant malignancies. STATEMENT OF SIGNIFICANCE: SETBP1 mutations are markers of high-risk myeloid malignancies, but we lack any targeted therapies to improve outcomes. In this study, we identify MYST acetyltransferases as key drivers of mutant SETBP1-driven transcription. MYST inhibitors are highly effective against SETBP1-mutant leukemia and represent a promising avenue for clinical translation.