TSLP-induced Mechanisms and Potential Therapies for CRLF2 B-cell Acute Lymphoblastic Leukemia
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.
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
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