HDAC1 is a required cofactor of CBFb-SMMHC and a potential therapeutic target in inversion 16 acute myeloid leukemia

Lisa E. Richter, Yiqian Wang, Michelle E. Becker, Rachel A. Coburn, Jacob T. Williams, Catalina Amador, R. Katherine Hyde

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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, CBFb-SMMHC, forms a heterodimer with the key hematopoietic transcription factor RUNX1. Although CBFb-SMMHC was previously thought to dominantly repress RUNX1, recent work suggests that CBFb-SMMHC functions together with RUNX1 to activate transcription of specific target genes.However, the mechanismof 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 CBFb-SMMHC, colocalizes with RUNX1 and CBFb-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 CBFb-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 CBFb- 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 CBFb-SMMHC and a potential therapeutic target in inv (16) AML.

Original languageEnglish (US)
Pages (from-to)1241-1252
Number of pages12
JournalMolecular Cancer Research
Volume17
Issue number6
DOIs
StatePublished - Jun 1 2019

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ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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