Targeting endoplasmic reticulum stress-induced apoptosis to reduce health disparity in high-risk B-cell acute lymphoblastic leukemia in Hispanic/Latino children

Abstract B-cell Acute Lymphoblastic Leukemia (ALL) is the most common childhood malignancy. The death rate from B-ALL in Hispanic/Latino (H/L) is 40% higher than in non-Hispanic whites (NHW) after correcting socioeconomic factors. Deletion of one IKZF1 allele is highly increased H/L children, which provides a biological rationale for the worse prognosis of B-ALL in this population. The very high incidence (31% in all children and 65% in children ≥10 yrs) 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. Identification of IKAROS target genes in B-ALL of H/L children is essential to understand the specificity of B-ALL pathogenesis in those children and develop the targeted treatment 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 promoter of eukaryotic elongation factor 2 kinase (eEF2K). eEF2K regulates protein synthesis, cell cycle progression and malignant transformation. The activity of eEF2K is increased in human malignancies, including B-ALL, and eEF2K is a critical regulator of endoplasmic reticulum (ER) stress-induced autophagy and apoptosis in tumor cells. The role of IKAROS in the regulation of eEF2K expression in B-ALL of H/L children was established using gain-of-function and loss-of-function experiments. Overexpression of IKZF1 in H/L B-ALL cells results in reduced expression of eEF2K, while IKZF1 knock-down results in increased transcription of eEF2K in H/L B-ALL. Since IKAROS function in leukemia is regulated by pro-oncogenic Casein Kinase 2 (CK2), we tested whether CK2 can control the ability of IKAROS to regulate the expression of eEF2K in H/L B-ALL. Increased expression of CK2 in H/L B-ALL results in increased expression of the eEF2K gene due to the loss of IKAROS binding to the promoter of the eEF2K genes. Inhibition of CK2 with shRNA and/or a specific CK2 inhibitor, CX-4945, restores IKAROS binding to promoter of eEF2K in high-risk B-ALL with deletion of one IKZF1 allele in H/L children. Restoration of IKAROS binding to promoter of eEF2K in high-risk B-ALL in H/L children results in reduced expression of this gene. This was associated with increased sensitivity to Akt inhibition by MK-2206. Combination treatment with CK2 inhibitor and MK-2206 showed a synergistic effect on B-ALL cells from H/L children. In summary, presented data demonstrate that IKAROS and CK2 regulate ER stress-induced apoptosis via regulation of eEF2K expression in high-risk B-ALL in Hispanic/Latino children. Results suggest that targeting ER stress-induced apoptosis in combination with CK2 inhibitors can be an efficient treatment to reduce the health disparity in survival for Hispanic/Latino children with B-ALL. Citation Format: Sinisa Dovat, Yali Ding, Dhimant Desai, Arati Sharma. Targeting endoplasmic reticulum stress-induced apoptosis to reduce health disparity in high-risk B-cell acute lymphoblastic leukemia in Hispanic/Latino children [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A088.