{"id":{"repo_id":"uwo","oai_identifier":"oai:uwo.scholaris.ca:20.500.14721/37700"},"canonical_url":"https://search.dev.ndltd.org/etd/uwo/oai:uwo.scholaris.ca:20.500.14721/37700","repository":{"repo_id":"uwo","name":"Western University","base_url":"https://uwo.scholaris.ca/server/oai/request"},"display":{"title":"Role of ETV5 Mutations in B Cell Acute Lymphoblastic Leukemia","abstract":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Yi, Joshua S"],"institution":"The University of Western Ontario","degree_name":"M Sc","degree_level":null,"degree_discipline":"Microbiology and Immunology","degree_department":null,"school":null,"contributors":[],"advisors":["DeKoter, Rodney P."],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-06-04","date_published":"2024-06-04","updated_at":"2026-07-27T21:55:56Z","subjects":["B cell acute lymphoblastic leukemia","ETV5","driver mutation","B cell","leukemia","cancer"],"languages":["en_ca"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/20.500.14721/37700","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["DeKoter, Rodney P."]},{"key":"dc:creator","label":"Author","values":["Yi, Joshua S"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2025-07-10T21:40:50Z"]},{"key":"dc:date.issued","label":"Date","values":["2024-06-04"]},{"key":"dc:publisher","label":"Institution","values":["The University of Western Ontario"]},{"key":"dc:type","label":"Dc Type","values":["thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Microbiology and Immunology"]},{"key":"thesis:degree_name","label":"Degree Name","values":["M Sc"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["B cell acute lymphoblastic leukemia","ETV5","driver mutation","B cell","leukemia","cancer"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en_ca"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/20.500.14721/37700"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Collaborative Specialization: Developmental Biology","The thesis cover page in the PDF document includes references to Western University’s previous institutional repository platform, known as Scholarship@Western, and links to that platform (beginning with ir.lib.uwo.ca). In citing or referring to this thesis, use the DOI or handle from this page instead. Sample citation: Author name, \"Thesis title.\" (Year). Western University Open Repository. https://doi.org/10.71858/123456."]},{"key":"dc:description.abstract","label":"Abstract","values":["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."]},{"key":"dc:title","label":"Title","values":["Role of ETV5 Mutations in B Cell Acute Lymphoblastic Leukemia"]}]}],"canonical_facts":{"dc:contributor.advisor":["DeKoter, Rodney P."],"dc:creator":["Yi, Joshua S"],"dc:date.accessioned":["2025-07-10T21:40:50Z"],"dc:date.issued":["2024-06-04"],"dc:description":["Collaborative Specialization: Developmental Biology","The thesis cover page in the PDF document includes references to Western University’s previous institutional repository platform, known as Scholarship@Western, and links to that platform (beginning with ir.lib.uwo.ca). In citing or referring to this thesis, use the DOI or handle from this page instead. Sample citation: Author name, \"Thesis title.\" (Year). Western University Open Repository. https://doi.org/10.71858/123456."],"dc:description.abstract":["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."],"dc:identifier.uri":["https://hdl.handle.net/20.500.14721/37700"],"dc:language.iso":["en_ca"],"dc:publisher":["The University of Western Ontario"],"dc:subject":["B cell acute lymphoblastic leukemia","ETV5","driver mutation","B cell","leukemia","cancer"],"dc:title":["Role of ETV5 Mutations in B Cell Acute Lymphoblastic Leukemia"],"dc:type":["thesis"],"thesis:degree_discipline":["Microbiology and Immunology"],"thesis:degree_name":["M Sc"]},"updated_at":"2026-07-27T21:55:56Z"}