Electronic Thesis and Dissertation Repository

Thesis Format



Master of Science


Microbiology and Immunology

Collaborative Specialization

Developmental Biology


DeKoter, Rodney P.


B cell acute lymphoblastic leukemia (B-ALL) develops through the acquisition of driver mutations that impair cell differentiation and promote proliferation. In human B-ALL, mutations in E26 transformation-specific (ETS) transcription factors are commonly reported. Our laboratory studies a mouse model of B-ALL in which leukemia is driven by deletion of genes encoding the ETS transcription factors, PU.1 and Spi-B. Whole exome sequencing was performed on PU.1-/Spi-B null leukemias to identify additional driver mutations and showed that there were frequent mutations in ETS variant transcription factor 5 (ETV5), which included R392P, V444I, and T505A. It was hypothesized that ETV5 mutations alter its ability to bind target DNA sequences, resulting in altered gene expression that promotes leukemia. Electrophoretic mobility shift assays demonstrated that R392P and V444I impaired the ability of ETV5 to bind to its cognate binding site (5’-CCGGAA-3’). In contrast, T505A did not change cognate DNA-binding activity. Cell counting and proliferation assays demonstrated that forced expression of T505A in PU.1-/Spi-B null primary bone marrow cells in vitro conferred a proliferative advantage. No differences were observed for R392P and V444I. Using RNA-seq and gene set enrichment analysis, all mutations demonstrated altered gene expression and pathway enrichment. Notably, T505A was suggested to downregulate the p53 pathway. Moreover, the T505A mutation caused a decrease in the transcript expression of B cell translocation gene 2 (Btg2), which encodes the anti-proliferative protein, BTG2. Overall, we demonstrate that ETV5 mutations can alter DNA binding activity and gene expression to promote a leukemic phenotype. These findings enhance our understanding of the role of ETV5 in B-ALL development and progression.

Summary for Lay Audience

B cells are important cells that help to fight dangerous entities that enter our body. However, in certain situations, B cells can act abnormally and become cancerous. A common form of B cell cancer is B-cell acute lymphoblastic leukemia (B-ALL). While there are different ways that B cells can become cancerous, a common mechanism is through mutations in a group of proteins called E26 transformation-specific (ETS) transcription factors. Currently, our lab is studying a member of this group, called ETS translocation variant 5 (ETV5). We found that a particular mutation—T505A—promoted B cells towards a cancerous state. For example, this mutation caused B cells to grow at an abnormally fast rate, which is a common characteristic of many cancers. Not only that, this T505A mutation was also suggested to suppress a critical defense mechanism against cancer, called the p53 pathway. Overall, our studies suggest that this T505A mutation may cause B cells to become cancerous. Further research will allow us to determine how this mutation may promote cancer and provide new insight into treatment for B cell acute lymphoblastic leukemia.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

Available for download on Thursday, June 04, 2026