Abstract 6052: Metabolic consequences of casein kinase 2α inhibition in lymphoid leukemia

Abstract Overexpression of casein kinase 2α (CK2α) is a common feature in lymphoid leukemias. Constitutively active CK2α can disable transcriptional activity of lymphoid transcription factors like IKAROS that act as metabolic gatekeeper and limit the energy supply needed for oncogenic transformation of B cells. Our studies have shown that pharmacological inhibition of CK2α can restore the transcriptional activity of IKAROS and ablate leukemia. However, the role of CK2α in glucose metabolism has not been fully studied in B and T acute lymphoblastic leukemia (ALL). Therefore, in the present study we explored the metabolic alterations induced by the pharmacological inhibition of CK2α in B and T ALL. We studied the effect of CK2α inhibition using a specific inhibitor - CX4945 on cell proliferation, glucose utilization, lactate production, and intracellular ATP levels using established methods in human B-ALL (NALM6) cell line. Effect of CX4945 on glycolysis was studied using the Seahorse cell analyzer in human B (NALM6 and 697) and T (MOLT4 and 697) ALL cell lines. Metabolomics study was undertaken to analyze differential metabolite profiling in NALM6 cells treated with CX4945 compared to vehicle using LC-MS/MS based methods. Results showed that CX4945 induced apoptotic cell death in ALL cell lines with IC50 concentrations ranging between 4-10 µM. CX4945 treatment significantly affected the glucose consumption in NALM6 cells. Similarly, substantial decrease in intracellular ATP and lactate levels compared to vehicle was recorded. CK2α inhibition significantly decreased the glycolytic activity in B- and T-ALL cell lines. It was observed that glycolytic reserves were significantly decreased in 697 (3-fold), MOLT4 (4-fold), CEM (3-fold) cells incubated with CX4945 in comparison to vehicle. The principal component analysis from metabolomics study showed a clear separation between CX4945 and vehicle-treated NAML6 cells. Sixty-four statistically significant, differentially expressed metabolites were recorded in the study. Analyte classes included TCA cycle intermediates, nucleic acids and their precursors as well as glycolysis intermediates that were significantly affected by CK2α inhibition. In conclusion, our study shows that selective inhibition of CK2α by CX4945 caused energy deficiency and cell death in ALL cell lines. CK2 inhibition targeted the key energy dependent pathway by rendering ALL cells inefficient in utilizing glucose and operating glycolysis for generation of cellular energy. These results offer a new mechanistic understanding of CK2α inhibition mediated ablation of ALL. Citation Format: Diwakar Bastihalli Tukaramrao, Arati Sharma, Dhimant Desai, Sinisa Dovat. Metabolic consequences of casein kinase 2α inhibition in lymphoid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6052.