Novel targeted therapy to reduce health disparities in pediatric leukemia

ABSTRACT Hispanic/Latino (H/L) children and adolescents have a 40% higher death rate than non-Hispanic whites (NHW) after correcting socioeconomic factors. Recently, we identified a highly increased incidence of deletion of one IKZF1 allele in H/L children, which provided a biological rationale for the worse prognosis of B-cell acute lymphoblastic leukemia (B-ALL) in this population. The very high incidence (29%) makes the deletion of one IKZF1 allele the most frequent genetic alteration that confers adverse prognosis in B-ALL in H/L children. Thus, understanding the biological basis for resistance to chemotherapy and developing novel therapies to treat B-ALL with deletion of one IKZF1 allele will reduce the health disparity in survival for Hispanic/Latino children with ALL. The IKZF1 gene encodes a DNA-binding protein, IKAROS, which functions as a transcriptional regulator. Our published data showed that, in B-ALL, IKAROS phosphorylation by the oncogenic Casein Kinase II (CK2) reduces IKAROS DNA-binding affinity and abolishes its function as a transcriptional regulator. Our new preliminary data suggest that CK2 impairs the ability of IKAROS to repress transcription of two key genes involved in the thiopurine pathway, resistance to 6-mercaptopurine (6-MP) treatment, and relapse: TPMT and NT5C2. Treatment with CK2-specific inhibitor, CX-4945, restores IKAROS-mediated repression of the TPMT and NT5C2 genes in primary B-ALL cells from H/L children. In vitro treatment of B-ALL with CX-4945 in combination with 6-MP exhibits a strong synergistic cytotoxic effect. Our overall hypothesis is that overexpression of CK2 in high-risk B-ALL of H/L children impairs IKAROS’ ability to transcriptionally repress the genes that regulate resistance to treatment with 6-MP, and that CK2 inhibition will restore IKAROS function as a transcriptional repressor of these genes, resulting in increased sensitivity to 6-MP. This hypothesis will be tested in vivo, using various biological models. We will define the mechanism through which IKAROS regulates the thiopurine pathway in primary B-ALL cells from H/L children. The effect of increased CK2 expression on thiopurine pathway and IKAROS function will be analyzed in patient-derived xenografts (PDXs), generated from B-ALL from H/L children. Finally, we will establish the therapeutic efficacy of combination treatment with CK2 inhibitor (CX-4945) and 6-mercaptopurine (6-MP) in a preclinical model of B-ALL from H/L children. Results of the project will provide a novel insight into the regulation of the thiopurine pathway and help develop novel treatments for high-risk B-ALL in H/L children and reduce childhood cancer health disparities.