Author ORCID Identifier

https://orcid.org/0000-0001-7166-1322

Date of Graduation

5-2018

Document Type

Thesis (MS)

Program Affiliation

Epigenetics and Molecular Carcinogenesis

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Margarida Santos

Committee Member

Michelle Barton

Committee Member

Xiaobing Shi

Committee Member

George Eisenhoffer

Committee Member

Zeev Estrov

Abstract

Treatment for acute myeloid leukemia (AML) has changed little in the past four decades. For the majority of AML patients, current treatment options include chemotherapy and allogeneic stem cell transplants, which also involves high-dose chemotherapy or radiation treatment. These options have little success in the long-run, as only an estimated 26% of patients survive five years post-diagnosis. In efforts to address this low survival rate, interest has increased for targeting epigenetic pathways in AML. This focus stems from the discovery that AML is frequently driven by blockades on hematopoietic stem cell differentiation, which involves a series of coordinated epigenetic changes. Given its reported roles as an epigenetic reader, stem cell regulator, and known oncogene, we investigated TRIM24 for putative relevance in AML. Expression data from previous studies have also suggested roles for TRIM24 in chronic myeloid leukemia and acute lymphocytic leukemia; however, no studies to date have reported measurements of TRIM24 in AML from an in vivo system. Here, we report that low TRIM24 mRNA expression in human AML patients (in TCGA) correlates with poor survival. Additionally, this association was found to be independent of gene expression signatures of prognostic significance, such as Gentles leukemic stem cell signature. Furthermore, loss of Trim24 in murine, MLL-AF9-driven AML worsened survival and increased leukemic stem cell numbers, while having no observed effects on normal hematopoiesis. These results lay the groundwork for future investigations of the role of TRIM24 in AML, which has the potential to aid development of novel therapeutic strategies.

Keywords

Leukemia, AML, Hematopoiesis, Hematopoietic, Stem cell, MLL, MLL-fusion, MLL-AF9

Available for download on Friday, April 12, 2019

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