Childhood CRLF2 B-cell Acute Lymphoblastic Leukemia (CRLF2 B-ALL) is a high-risk form of leukemia that is associated with poor patient survival outcomes. CRLF2 B-ALL is five times more prevalent in Hispanic children than others and is associated with a higher rate of relapse, thus contributing significantly to childhood cancer health disparities. This disease occurs due to alterations of the CRLF2 gene, leading to overexpression of the CRLF2 protein- a component of the receptor signaling complex for the cytokine Thymic Stromal LymphoPoietin (TSLP) on the surface of B-ALL cells. TSLP has been shown to induce proliferation of human and mouse B-cell precursors via activation of the JAK-STAT5 and more recently the PI3K/AKT/mTOR pathways. However, the mechanisms by which TSLP-CRLF2 interactions contribute to high-risk leukemia have not been elucidated. Therefore the objective of our studies was to elucidate the TSLP-induced mechanisms that contribute to high-risk CRLF2 B-ALL and to evaluate promising drug candidates to target high-risk B-ALL. Based on literature findings and preliminary data, we hypothesized that TSLP contributes to CRLF2 B-ALL by increasing proliferation and/or survival of leukemia cells via regulation of genes downstream of CRLF2 pathway activation. This hypothesis was tested using experiments developed under the following specific aims:- Aim 1: Optimize the novel hTSLP+/- xenograft model for use in defining the role of TSLP in CRLF2 B-ALL; Aim 2: Identify TSLP-induced cellular and molecular mechanisms that contribute to CRLF2 B-ALL; Aim 3: Assess candidate drugs’ efficacy against high-risk B-ALL. Results from the studies conducted to address the specific aims show that 1) the hTSLP+/hTSLP- mouse model produces detectable levels of hTSLP, which activates CRLF2 and expands normal B-cells and activates the mTOR cell survival pathway in CRLF2 B-ALL cells in vivo; 2) cellular assays of apoptosis along with gene expression data demonstrate that TSLP regulates the expression of genes that promote cell death and survival of CRLF2 B-ALL cells in vivo and in vitro; 3) drug efficacy studies performed on high-risk leukemia cells using several drug candidates demonstrate that the Mcl-1 inhibitor MIM1 and the Novomedix drug series induced cell death in CRLF2 B-ALL and Nalm6 cells respectively. Taken together, the data provide evidence that TSLP regulates cell survival mechanisms in CRLF2 B-ALL cells and provides a rationale for the use of combination therapies that include drugs which target cell survival molecules and/or cellular functions regulated by TSLP.
","abstract_html":"<p>Childhood CRLF2 B-cell Acute Lymphoblastic Leukemia (CRLF2 B-ALL) is a high-risk form of leukemia that is associated with poor patient survival outcomes. CRLF2 B-ALL is five times more prevalent in Hispanic children than others and is associated with a higher rate of relapse, thus contributing significantly to childhood cancer health disparities. This disease occurs due to alterations of the CRLF2 gene, leading to overexpression of the CRLF2 protein- a component of the receptor signaling complex for the cytokine Thymic Stromal LymphoPoietin (TSLP) on the surface of B-ALL cells. TSLP has been shown to induce proliferation of human and mouse B-cell precursors via activation of the JAK-STAT5 and more recently the PI3K/AKT/mTOR pathways. However, the mechanisms by which TSLP-CRLF2 interactions contribute to high-risk leukemia have not been elucidated. Therefore the objective of our studies was to elucidate the TSLP-induced mechanisms that contribute to high-risk CRLF2 B-ALL and to evaluate promising drug candidates to target high-risk B-ALL. Based on literature findings and preliminary data, we hypothesized that TSLP contributes to CRLF2 B-ALL by increasing proliferation and/or survival of leukemia cells via regulation of genes downstream of CRLF2 pathway activation. This hypothesis was tested using experiments developed under the following specific aims:- Aim 1: Optimize the novel hTSLP+/- xenograft model for use in defining the role of TSLP in CRLF2 B-ALL; Aim 2: Identify TSLP-induced cellular and molecular mechanisms that contribute to CRLF2 B-ALL; Aim 3: Assess candidate drugs’ efficacy against high-risk B-ALL. Results from the studies conducted to address the specific aims show that 1) the hTSLP+/hTSLP- mouse model produces detectable levels of hTSLP, which activates CRLF2 and expands normal B-cells and activates the mTOR cell survival pathway in CRLF2 B-ALL cells in vivo; 2) cellular assays of apoptosis along with gene expression data demonstrate that TSLP regulates the expression of genes that promote cell death and survival of CRLF2 B-ALL cells in vivo and in vitro; 3) drug efficacy studies performed on high-risk leukemia cells using several drug candidates demonstrate that the Mcl-1 inhibitor MIM1 and the Novomedix drug series induced cell death in CRLF2 B-ALL and Nalm6 cells respectively. Taken together, the data provide evidence that TSLP regulates cell survival mechanisms in CRLF2 B-ALL cells and provides a rationale for the use of combination therapies that include drugs which target cell survival molecules and/or cellular functions regulated by TSLP.</p>","abstract_has_math":false,"creators":["Francis, Olivia L."],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation","degree_discipline":"Basic Sciences","degree_department":null,"school":null,"contributors":["Payne, Kimberly J.","Dovat, Sinisa","Kearns-Jonker, Mary","Oberg, Kerby","Soto-Wegner, Ubaldo","Weldon, David J."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2015,"date_issued":"2015-06-01T07:00:00Z","date_published":"2015-06-01T07:00:00Z","updated_at":"2026-07-24T02:52:27Z","subjects":["Anatomy","Diseases","Genetic Phenomena","Hemic and Lymphatic Diseases","Medical Anatomy","Precursor Cell Lymphoblastic Leukemia-Lymphoma; Cytokines; Receptor - Cytokine; Cell Line - Tumor; Bone Marrow Cells; Stromal Cells; Gene Rearrangement - B-Lymphocyte - Heavy Chain; Immunoglobulin Class Switching; Protein Kinase Inhibitors; Janus Kinases; Signal Transduction","Hispanic Children; Rate of Relapse; Childhood Cancer Health Disparities; Thymic Stromal LymphoPoietin"],"languages":["English"],"rights":["This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://scholarsrepository.llu.edu/etd/282","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Payne, Kimberly J.","Dovat, Sinisa","Kearns-Jonker, Mary","Oberg, Kerby","Soto-Wegner, Ubaldo","Weldon, David J."]},{"key":"dc:creator","label":"Author","values":["Francis, Olivia L."]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"thesis:degree_discipline","label":"Discipline","values":["Basic Sciences"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Anatomy","Diseases","Genetic Phenomena","Hemic and Lymphatic Diseases","Medical Anatomy","Precursor Cell Lymphoblastic Leukemia-Lymphoma; Cytokines; Receptor - Cytokine; Cell Line - Tumor; Bone Marrow Cells; Stromal Cells; Gene Rearrangement - B-Lymphocyte - Heavy Chain; Immunoglobulin Class Switching; Protein Kinase Inhibitors; Janus Kinases; Signal Transduction","Hispanic Children; Rate of Relapse; Childhood Cancer Health Disparities; Thymic Stromal LymphoPoietin"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["English"]},{"key":"dc:rights","label":"Dc Rights","values":["This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://scholarsrepository.llu.edu/etd/282"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Childhood CRLF2 B-cell Acute Lymphoblastic Leukemia (CRLF2 B-ALL) is a high-risk form of leukemia that is associated with poor patient survival outcomes. CRLF2 B-ALL is five times more prevalent in Hispanic children than others and is associated with a higher rate of relapse, thus contributing significantly to childhood cancer health disparities. This disease occurs due to alterations of the CRLF2 gene, leading to overexpression of the CRLF2 protein- a component of the receptor signaling complex for the cytokine Thymic Stromal LymphoPoietin (TSLP) on the surface of B-ALL cells. TSLP has been shown to induce proliferation of human and mouse B-cell precursors via activation of the JAK-STAT5 and more recently the PI3K/AKT/mTOR pathways. However, the mechanisms by which TSLP-CRLF2 interactions contribute to high-risk leukemia have not been elucidated. Therefore the objective of our studies was to elucidate the TSLP-induced mechanisms that contribute to high-risk CRLF2 B-ALL and to evaluate promising drug candidates to target high-risk B-ALL. Based on literature findings and preliminary data, we hypothesized that TSLP contributes to CRLF2 B-ALL by increasing proliferation and/or survival of leukemia cells via regulation of genes downstream of CRLF2 pathway activation. This hypothesis was tested using experiments developed under the following specific aims:- Aim 1: Optimize the novel hTSLP+/- xenograft model for use in defining the role of TSLP in CRLF2 B-ALL; Aim 2: Identify TSLP-induced cellular and molecular mechanisms that contribute to CRLF2 B-ALL; Aim 3: Assess candidate drugs’ efficacy against high-risk B-ALL. Results from the studies conducted to address the specific aims show that 1) the hTSLP+/hTSLP- mouse model produces detectable levels of hTSLP, which activates CRLF2 and expands normal B-cells and activates the mTOR cell survival pathway in CRLF2 B-ALL cells in vivo; 2) cellular assays of apoptosis along with gene expression data demonstrate that TSLP regulates the expression of genes that promote cell death and survival of CRLF2 B-ALL cells in vivo and in vitro; 3) drug efficacy studies performed on high-risk leukemia cells using several drug candidates demonstrate that the Mcl-1 inhibitor MIM1 and the Novomedix drug series induced cell death in CRLF2 B-ALL and Nalm6 cells respectively. Taken together, the data provide evidence that TSLP regulates cell survival mechanisms in CRLF2 B-ALL cells and provides a rationale for the use of combination therapies that include drugs which target cell survival molecules and/or cellular functions regulated by TSLP.
"]},{"key":"dc:title","label":"Title","values":["TSLP-induced Mechanisms and Potential Therapies for CRLF2 B-cell Acute Lymphoblastic Leukemia"]}]}],"canonical_facts":{"dc:contributor":["Payne, Kimberly J.","Dovat, Sinisa","Kearns-Jonker, Mary","Oberg, Kerby","Soto-Wegner, Ubaldo","Weldon, David J."],"dc:creator":["Francis, Olivia L."],"dc:description.abstract":["Childhood CRLF2 B-cell Acute Lymphoblastic Leukemia (CRLF2 B-ALL) is a high-risk form of leukemia that is associated with poor patient survival outcomes. CRLF2 B-ALL is five times more prevalent in Hispanic children than others and is associated with a higher rate of relapse, thus contributing significantly to childhood cancer health disparities. This disease occurs due to alterations of the CRLF2 gene, leading to overexpression of the CRLF2 protein- a component of the receptor signaling complex for the cytokine Thymic Stromal LymphoPoietin (TSLP) on the surface of B-ALL cells. TSLP has been shown to induce proliferation of human and mouse B-cell precursors via activation of the JAK-STAT5 and more recently the PI3K/AKT/mTOR pathways. However, the mechanisms by which TSLP-CRLF2 interactions contribute to high-risk leukemia have not been elucidated. Therefore the objective of our studies was to elucidate the TSLP-induced mechanisms that contribute to high-risk CRLF2 B-ALL and to evaluate promising drug candidates to target high-risk B-ALL. Based on literature findings and preliminary data, we hypothesized that TSLP contributes to CRLF2 B-ALL by increasing proliferation and/or survival of leukemia cells via regulation of genes downstream of CRLF2 pathway activation. This hypothesis was tested using experiments developed under the following specific aims:- Aim 1: Optimize the novel hTSLP+/- xenograft model for use in defining the role of TSLP in CRLF2 B-ALL; Aim 2: Identify TSLP-induced cellular and molecular mechanisms that contribute to CRLF2 B-ALL; Aim 3: Assess candidate drugs’ efficacy against high-risk B-ALL. Results from the studies conducted to address the specific aims show that 1) the hTSLP+/hTSLP- mouse model produces detectable levels of hTSLP, which activates CRLF2 and expands normal B-cells and activates the mTOR cell survival pathway in CRLF2 B-ALL cells in vivo; 2) cellular assays of apoptosis along with gene expression data demonstrate that TSLP regulates the expression of genes that promote cell death and survival of CRLF2 B-ALL cells in vivo and in vitro; 3) drug efficacy studies performed on high-risk leukemia cells using several drug candidates demonstrate that the Mcl-1 inhibitor MIM1 and the Novomedix drug series induced cell death in CRLF2 B-ALL and Nalm6 cells respectively. Taken together, the data provide evidence that TSLP regulates cell survival mechanisms in CRLF2 B-ALL cells and provides a rationale for the use of combination therapies that include drugs which target cell survival molecules and/or cellular functions regulated by TSLP.
"],"dc:identifier":["https://scholarsrepository.llu.edu/etd/282"],"dc:language":["English"],"dc:rights":["This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights."],"dc:subject":["Anatomy","Diseases","Genetic Phenomena","Hemic and Lymphatic Diseases","Medical Anatomy","Precursor Cell Lymphoblastic Leukemia-Lymphoma; Cytokines; Receptor - Cytokine; Cell Line - Tumor; Bone Marrow Cells; Stromal Cells; Gene Rearrangement - B-Lymphocyte - Heavy Chain; Immunoglobulin Class Switching; Protein Kinase Inhibitors; Janus Kinases; Signal Transduction","Hispanic Children; Rate of Relapse; Childhood Cancer Health Disparities; Thymic Stromal LymphoPoietin"],"dc:title":["TSLP-induced Mechanisms and Potential Therapies for CRLF2 B-cell Acute Lymphoblastic Leukemia"],"thesis:degree_discipline":["Basic Sciences"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T02:52:27Z"}