Hispanic children have a 39% higher death rate due to ALL than white children. A major cause of this health disparity in survival is the lack of therapies that specifically target the high-risk B-ALL caused by deregulated CRLF2 (CRLF2-d). Genetic defects resulting in B cells that overexpress the cytokine receptor component, CRLF2, lead to malignant transformation and high-risk CRLF2-d B-ALL with poor prognosis. B-ALL arising from CRLF2-d is five times more frequent among children of Hispanic/Latino ethnicity than others. CRLF2 is part of a signaling receptor activated by ligation with the cytokine TSLP. TSLP has been reported to expand B- ALL cells and to protect them from mTOR inhibitors. Human B-ALL-mouse xenograft models that mimic the in vivo BM environment are the model of choice for identifying therapies that target the mechanisms of chemoresistance that are characteristic of high-risk B-ALL. However, mouse TSLP does not interact with human CRLF2. Thus, existing xenograft models of B-ALL are inadequate for studies of CRLF2-d B-ALL because they do not provide the human TSLP that is required to induce CRLF2-mediated signals. The development of xenograft models of CRLF2 function in B-ALL are essential for identifying therapies that will selectively target CRLF2-d and reduce the health disparity in survival for Hispanic children due to high-risk CRLF2-d B-ALL. The objective of this proposal is to develop an in vivo model of CRLF2 function in B-ALL by expressing human TSLP (hTSLP) in a xenograft model of B-ALL and to use this model to investigate CRLF-2- TSLP interactions as a therapeutic target for high risk CRLF2-d B-ALL. We will achieve this objective through the following aims:
Specific Aim 1 : Develop a human-mouse xenograft model to identify therapies that will specifically target CRLF2-d B-ALL. We will: 1.1. Engineer immunodeficient mice for lentiviral expression of human hTSLP. 1.2.Optimize the human-mouse xenograft model system for engraftment with CRLF2-d B- ALL cells. Our overarching hypothesis is that TSLP induces CRLF2-mediated signals that are responsible for the disease progression and chemoresistance of CRLF2-d B-ALL that results in poor survival for Hispanic children with B-ALL. To test this hypothesis we will:
Specific Aim 2. Determine the impact of CRLF2 ligation on the progression of CRLF2-d B-ALL. Using the hTSLP+/- xenograft model system we will 2.2 Determine the extent of bone marrow disease. 2.3 Evaluate TSLP receptor signaling in B-ALL cells. The xenograft model of CRLF2 function in B-ALL that we will develop in this application will be essential for identifying therapies that will selectively target CRLF2-d and reduce the health disparity in survival for Hispanic children due to high-risk CRLF2-d B-ALL.
Hispanic children disproportionately develop and die from high-risk B-cell acute lymphoblastic leukemia (B- ALL). Defects in B cells that cause increased levels of the growth factor receptor CRLF2 are five times more frequent among children of Hispanic/Latino ethnicity than others and contribute to their increased death from high-risk B-ALL. We will develop a unique animal model that allows us to study and target the mechanism by which CRLF2 contributes to leukemia and reduce health disparities in Hispanic childhood B-ALL.
