Graduation Date

Fall 12-20-2019

Document Type


Degree Name

Doctor of Philosophy (PhD)


Biochemistry & Molecular Biology

First Advisor

Kate Hyde


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 (MYH11), forming the oncogene CBFB-MYH11. The expressed protein, CBFβ-SMMHC, forms a heterodimer with the key hematopoietic transcription factor RUNX1. Although CBFβ-SMMHC was previously thought to dominantly repress RUNX1, recent work suggests that CBFβ-SMMHC functions together with RUNX1 to activate transcription of specific target genes.

Targeting the activity of CBFβ-SMMHC is a promising approach for treating inv(16) AML, although currently there are no inhibitors of CBFβ-SMMHC ready for clinical use. An alternative approach is to indirectly target the fusion protein by inhibiting the activity of other proteins which are recruited to CBFβ-SMMHC and are required for its activity. One possible target is the epigenetic regulator histone deacetylase 1 (HDAC1), which was previously shown to colocalize with CBFβ-SMMHC on gene promoters. We hypothesized that HDAC1 was recruited to the CBFβ-SMMHC:RUNX1 complex and inhibitors of HDAC1 could be used to indirectly target its leukemogenic activity.

In this study, we demonstrate that HDAC1 forms a complex with CBFβ-SMMHC, confirmed its colocalization with RUNX1 and CBFβ-SMMHC on the promoters of known fusion protein target genes, and determined that Hdac1 is required for expression of these genes. These results imply that HDAC1 is an important component of the CBFβ-SMMHC transcriptional complex, and that leukemia cells expressing the fusion protein may be sensitive to treatment with HDAC1 inhibitors. Both Hdac1 knockdown and treatment with the HDAC1 selective inhibitor entinostat in vitro results in a decrease in colony-forming ability and an increase in differentiation in CBFβ-SMMHC+ cells, implying that HDAC1 is required to maintain the differentiation block in the leukemia cells. Using a knock-in mouse model expressing CBFβ-SMMHC, we found that in vivo treatment with entinostat decreased leukemic burden and induced differentiation and apoptosis of leukemia cells. Importantly, entinostat treatment specifically targeted the leukemia cells with minimal toxicity to normal cells. We also tested the same treatment strategy on survival of the mice but found that leukemia cells were able to continue to grow after cessation of treatment. Overall, our results demonstrate the strict requirement for HDAC1 in CBFβ-SMMHC+ cells and reveal that it is a promising therapeutic target for treatment of inv(16) AML.