Mutations in SETBP1 are associated with adverse prognosis in myeloid malignancies. These mutations stabilize the SETBP1 protein, driving increased expression of a progenitor-associated gene expression program through incompletely described mechanisms. A proteomic screen revealed interactions between SETBP1 and MYST acetyltransferase complexes, including the catalytic subunits-KAT6A and KAT7. In cell line and primary hematopoietic models, mutant SETBP1 increased the localization of MYST complexes at known SETBP1 target genes, including the HOXA cluster, in which they were shown to drive increased histone acetylation and gene expression. Treatment of SETBP1D868N-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 hematologic control and increased survival. MYST inhibition was also highly effective against a SETBP1-mutant patient-derived xenograft model. These studies identify MYST acetyltransferases as promising therapeutic targets in SETBP1-mutant malignancies.
Significance: SETBP1 mutations are markers of high-risk myeloid malignancies, but targeted therapies to improve outcomes in these patient populations are limited. In this study, we identified MYST acetyltransferases as key mediators of mutant SETBP1-driven transcription and showed that MYST inhibitors are highly effective against SETBP1-mutant leukemia models. See related commentary by Soto and Gritsman, p. 506.
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