Publication Date

2019-04-08

Availability

Embargoed

Embargo Period

2021-04-07

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Biochemistry and Molecular Biology (Medicine)

Date of Defense

2019-03-07

First Committee Member

Fengchun Yang

Second Committee Member

Mingjiang Xu

Third Committee Member

Luisa Cimmino

Abstract

DNA methylation is a defining feature with widespread involvement in many biological processes. Recent studies showed that dysregulated DNA methylation not only involves pathological processes and development, but also demonstrates dynamic feature in both locus-specific and genetic lesions-specific manner. AML1-ETO, a fusion protein encoded by t(8;21), one of the most frequent karyotype abnormalities in Acute Myeloid Leukemia (AML), was observed in proximately 10%~15% of human AMLs, and partially served as a diagnostic criterion for M2 subtype. However, AML1-ETO itself is not sufficient in promoting leukemia. In this study, we generated an in vivomouse model harboring both AML1-ETOconditional knockin and Tet1conditional knockout and observed a synergistic effect in leukemogenesis. Specifically, short survival was observed in mice with both Tet1loss and AML1-ETOexpression, with accelerated pathogenesis of myeloid malignancies, including myeloid leukemia with maturation, MPD-like leukemia and erythroid leukemia. The significance of this study lies in the discovery of synergistic effect between dysregulated DNA methylation mediated by Tet1loss and the expression of AML1-ETO fusion protein, paving the way for further mechanistic study and providing an in vivomodel for the testing of therapeutic agents.

Keywords

Tet1; AML1-ETO; leukemogenesis

Available for download on Wednesday, April 07, 2021

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