Abstract 4167: CK2 inhibition restores IKAROS-mediated metabolic control and induces cell death in acute lymphoblastic leukemia

Abstract The transcription factor IKAROS functions as a critical metabolic gatekeeper in B cells by regulating glucose metabolism and the pentose phosphate pathway (PPP). In lymphoid leukemias, casein kinase 2α (CK2α) overexpression impairs IKAROS function, leading to dysregulated cellular metabolism. This study investigated the metabolic consequences of CK2α inhibition in B- and T-cell acute lymphoblastic leukemia (ALL). Treatment of ALL cell lines with the CK2 inhibitor CX4945 resulted in significant cell death, with IC50 values ranging from 4-10 µM. In NALM6 cells, CK2α inhibition led to increased reactive oxygen species (ROS), decreased NADPH/NADP+ ratio, and reduced glucose consumption by 40%. Additionally, CX4945 treatment significantly decreased both glycolytic activity and mitochondrial respiration in ALL cell lines (NALM6, 697, MOLT4 and CEM). Metabolomic analysis revealed 64 differentially expressed metabolites between CX4945-treated and vehicle-treated NALM6 cells, with notable reductions in glycolytic intermediates. These findings demonstrate that CK2α inhibition effectively restores IKAROS-mediated metabolic control, leading to energy deficiency and increased oxidative stress in ALL cells. This work provides evidence that targeting the CK2-IKAROS axis represents a promising therapeutic strategy for ALL through metabolic modulation. Citation Format: Diwakar Bastihalli Tukaramrao, Arati Sharma, Dhimant Desai, Sinisa Dovat. CK2 inhibition restores IKAROS-mediated metabolic control and induces cell death in acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4167.