Abstract PR-12: Novel targeted combination therapy to reduce health disparity in high-risk B-cell acute lymphoblastic leukemia in Hispanic/Latino children

Abstract

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 an 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. The IKZF1 gene encodes a DNA-binding protein, Ikaros, which functions as a transcriptional regulator. Our goal is to determine the mechanism through which Ikaros regulates leukemia progression and to develop the novel therapy to treat B-ALL with deletion of one IKZF1 allele to reduce the health disparity in survival for H/L children with B-ALL. Global DNA-binding analysis of primary B-ALL cells from H/L children showed that Ikaros binds to the promoters of CDC20 and ANAPC7 genes. CDC20 and ANAPC7 genes have a critical role in mitosis progression and are essential for cellular proliferation. The role of Ikaros in the regulation of CDC20 and ANAPC7 expression in B-ALL of H/L children was established using gain-of-function and loss-of-function experiments. Overexpression of Ikaros in B-ALL cells results in reduced expression of CDC20 and ANAPC7, while Ikaros knock-down results in increased transcription of CDC20 and ANAPC7 in B-ALL. Since Ikaros function in hematopoietic malignancies is regulated by pro-oncogenic Casein Kinase 2 (CK2), we tested whether CK2 can control the ability of Ikaros to regulate the expression of CDC20 and ANAPC7 in B-ALL. Increased expression of CK2 in B-ALL results in increased expression of CDC20 and ANAPC7 genes due to the loss of Ikaros binding to the promoters of CDC20 and ANAPC7 genes. Inhibition of CK2 with shRNA and/or a specific CK2 inhibitor, CX-4945, restores Ikaros binding to promoters of CDC20 and ANAPC7 in high-risk B-ALL with deletion of one IKZF1 allele in H/L children. Restoration of Ikaros binding to promoters of CDC20 and ANAPC7 in high-risk B-ALL in H/L children results in reduced expression of these genes and cell cycle arrest. CK2 inhibition sensitizes B-ALL cells to treatment with an inhibitor of mitosis – vincristine. Combination treatment with CK2 inhibitor and vincristine showed a synergistic effect on B-ALL cells from H/L children. In summary, presented data demonstrate that IKAROS and CK2 regulate the progression of mitosis in high-risk B-ALL in Hispanic/Latino children. Results suggest that the combination treatment with CK2 inhibitors and vincristine can be an efficient novel treatment to reduce the health disparity in survival for Hispanic/Latino children with B-ALL. Citation Format: Sinisa Dovat, Dimant Desai, Arati Sharma, Chandrika Gowda. Novel targeted combination therapy to reduce health disparity in high-risk B-cell acute lymphoblastic leukemia in Hispanic/Latino children [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PR-12.