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Molecular Mechanisms of the DEK Protein in Leukemia

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Author

Summary, in English

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.

Department/s

Publishing year

2014

Language

English

Publication/Series

Lund University Faculty of Medicine Doctoral Dissertation Series

Volume

2014:71

Document type

Dissertation

Publisher

Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University

Topic

  • Hematology

Keywords

  • DEK
  • DEK-NUP214
  • fusion gene
  • acute myeloid leukemia
  • proliferation
  • mTOR
  • ChIP-seq

Status

Published

Supervisor

ISBN/ISSN/Other

  • ISSN: 1652-8220
  • ISBN: 978-91-7619-000-5

Defence date

12 June 2014

Defence time

09:15

Defence place

Belfragesalen, BMC D15, Klinikgatan 32, Lund, Sweden

Opponent

  • Sören Lehmann