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.
|Coats, Jacqueline S; Baez, Ineavely; Stoian, Cornelia et al. (2017) Expression of Exogenous Cytokine in Patient-derived Xenografts via Injection with a Cytokine-transduced Stromal Cell Line. J Vis Exp :|
|Francis, Olivia L; Milford, Terry-Ann M; Martinez, Shannalee R et al. (2016) A novel xenograft model to study the role of TSLP-induced CRLF2 signals in normal and malignant human B lymphopoiesis. Haematologica 101:417-26|
|Milford, Terry-Ann M; Su, Ruijun J; Francis, Olivia L et al. (2016) TSLP or IL-7 provide an IL-7R? signal that is critical for human B lymphopoiesis. Eur J Immunol 46:2155-61|
|Francis, Olivia L; Milford, Terry-Ann M; Beldiman, Cornelia et al. (2016) Fine-tuning patient-derived xenograft models for precision medicine approaches in leukemia. J Investig Med 64:740-4|
|Song, C; Pan, X; Ge, Z et al. (2016) Epigenetic regulation of gene expression by Ikaros, HDAC1 and Casein Kinase II in leukemia. Leukemia 30:1436-40|
|Wang, Haijun; Song, Chunhua; Ding, Yali et al. (2016) Transcriptional Regulation of JARID1B/KDM5B Histone Demethylase by Ikaros, Histone Deacetylase 1 (HDAC1), and Casein Kinase 2 (CK2) in B-cell Acute Lymphoblastic Leukemia. J Biol Chem 291:4004-18|
|Song, Chunhua; Gowda, Chandrika; Pan, Xiaokang et al. (2015) Targeting casein kinase II restores Ikaros tumor suppressor activity and demonstrates therapeutic efficacy in high-risk leukemia. Blood 126:1813-22|
|Payne, Kimberly J; Dovat, Sinisa (2014) G0S2--a new player in leukemia. Leuk Res 38:147-8|