Abstract B32: A novel preclinical model and targeted therapy to reduce pediatric leukemia health disparities
Authors: Payne Kimberly J. , Dovat Sinisa 
Published: May 2016

Data presented here identify a targeted therapy and a novel preclinical model for evaluating therapeutic efficacy to reduce pediatric cancer health disparities. Hispanic children are 1.24 times more likely to develop acute lymphoblastic leukemia (ALL) than non-Hispanic whites and that number rises to 2.09 by adolescence and early adulthood. A major contributor to this health disparity is a subtype of high-risk B cell precursor ALL called CRLF2 B-ALL. CRLF2 B-ALL occurs 5 times more often in Hispanic and Native American children than others and is also prevalent in adolescents and young adults. CRLF2 B-ALL is caused by genetic alterations leading to over expression of the cytokine receptor, CRLF2. CRLF2 activation stimulates proliferation of B cell precursors. Approximately 80% of CRLF2 B-ALL cases also have inactivating deletions or mutations in one allele of the (Ikaros) IKZF1 tumor suppressor gene. Ikaros normally represses genes responsible for cellular proliferation and Ikaros mutations are highly associated with relapse. Thus, our strategy is to identify therapies that target both the Ikaros and CRLF2 genetic alterations that are responsible for high-risk CRLF2 B-ALL and the health disparities caused by this disease. Our previous work has shown that Ikaros proteins can be inactivated Casein Kinase II (CK2) and that CK2 inhibitors can be used to restore normal levels of Ikaros activity from the remaining normal Ikaros allele in B-ALL. Patient-derived xenografts produced by transplanting leukemia cells from patients into immune deficient mice provide an in vivo model of disease that includes contributions of the background genetic landscape to health disparities diseases. Here we evaluated the in vivo therapeutic efficacy of the CK2-specific inhibitor, CX-4945, using patient-derived xenografts (PDX) produced by transplanting immune deficient mice with B-ALL cells from 2 different Hispanic pediatric patients with high-risk CRLF2 B-ALL. Survival was significantly prolonged (p&lt;.0002) in treated as compared to untreated PDX produced from both patients. Flow cytometry analysis also showed reduced leukemia cell number in bone marrow (BM) and in spleen of treated as compared to untreated PDX. These data provide evidence that CK2-specific inhibitors can be an effective therapy for targeting the Ikaros defect to restore Ikaros tumor suppressor activity in CRLF2 B-ALL in Hispanic patients. Our next step was the development of a preclinical model that would allow us to target the pathway activated by overexpressed CRLF2 in this disease. Biologically, CRLF2 acts as a receptor component for the cytokine, TSLP, which induces JAK2-STAT5 and PI3/AKT/mTOR pathway activation leading to increased production of B cell precursors. PDX models are possible because most cytokines produced in the mouse are active on human cells, however mouse TSLP is species-specific. Thus classic PDX models do not provide TSLP that can activate the CRLF2 receptor that is overexpressed in CRLF2 B-ALL. To address this hurdle we engineered PDX mice to express normal serum levels (12-32 pg/ml) of human TSLP (+T PDX mice). In vivo TSLP activity was validated and +T PDX were successfully generated using leukemia cells from two Hispanic pediatric patients with CRLF2 B-ALL. We are using this model in ongoing studies evaluate therapies that target the CRLF2 pathway. Future studies will be aimed at using the +T Hispanic Patient PDX preclinical model to evaluate the efficacy of therapies that target the CRLF2 pathway in combination with CK2 inhibitors to restore Ikaros tumor suppressor activity.

Citation Format: Kimberly J. Payne, Sinisa Dovat. A novel preclinical model and targeted therapy to reduce pediatric leukemia health disparities. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B32.