Molecular Mechanisms of the DEK Protein in Leukemia

Abstract: The DEK gene is upregulated in a growing number of cancers and translocated to form the DEK-NUP214 fusion gene in a subset of acute myeloid leukemia. In this thesis, we studied the cellular and molecular functions of the DEK and DEK-NUP214 proteins. We found that the expression of DEK is increased by the leukemia-associated fusion protein NUP98-HOXA9, suggesting that DEK may be a downstream mediator of its leukemogenic function. We also determined the genome-wide binding of the DEK protein, showing that DEK binds specifically to the trans-cription start sites of predominantly highly and ubiquitously expressed genes. Furthermore, we demonstrated that DEK can serve to either promote or repress the transcription of these genes. Finally, we discovered that the DEK-NUP214 fusion protein promotes cellular proliferation through increased expression of mTOR and enhanced activity of mTORC1. Pharmacological inhibition of mTOR selectively reversed the proliferative effect, suggesting that patients with the fusion gene may benefit from treatment with mTOR inhibitors. These findings elucidate the roles of DEK and DEK-NUP214 in cancer with implications for the treatment of the associated malignancies.