HDAC1 Is a Required Cofactor of CBF?-SMMHC and a Potential Therapeutic Target in Inversion 16 Acute Myeloid Leukemia.

ABSTRACT: Acute myeloid leukemia (AML) is a neoplastic disease characterized by the uncontrolled proliferation and accumulation of immature myeloid cells. A common mutation in AML is the inversion of chromosome 16 [inv (16)], which generates a fusion between the genes for core binding factor beta (CBFB) and smooth muscle myosin heavy chain gene (MYH11), forming the oncogene CBFB-MYH11. The expressed protein, CBF?-SMMHC, forms a heterodimer with the key hematopoietic transcription factor RUNX1. Although CBF?-SMMHC was previously thought to dominantly repress RUNX1, recent work suggests that CBF?-SMMHC functions together with RUNX1 to activate transcription of specific target genes. However, the mechanism of this activity or a requirement for additional cofactors is not known. Here, we show that the epigenetic regulator histone deacetylase 1 (HDAC1) forms a complex with CBF?-SMMHC, colocalizes with RUNX1 and CBF?-SMMHC on the promoters of known fusion protein target genes, and that Hdac1 is required for expression of these genes. These results imply that HDAC1 is an important component of the CBF?-SMMHC transcriptional complex, and that leukemia cells expressing the fusion protein may be sensitive to treatment with HDAC1 inhibitors. Using a knock-in mouse model expressing CBF?-SMMHC, we found that in vivo treatment with the HDAC1 inhibitor entinostat decreased leukemic burden, and induced differentiation and apoptosis of leukemia cells. Together, these results demonstrate that HDAC1 is an important cofactor of CBF?-SMMHC and a potential therapeutic target in inv (16) AML. IMPLICATIONS: This report describes a novel role for HDAC1 as a cofactor for the leukemogenic fusion protein CBF?-SMMHC and shows that inhibitors of HDAC1 effectively target leukemia cells expressing the fusion protein in vivo.

SUBMITTER: Richter LE 

PROVIDER: S-EPMC6548582 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature