Glutaminase Upregulation As a Mechanism of Chemotherapy Resistance in High-Risk Leukemia

Many types of cancers are characterized by elevated glutamine consumption. Glutaminase is a therapeutic target to arrest cancer cell development. Ikaros (IKZF1) is a DNA-binding, zinc finger protein that functions as a transcriptional regulator and a tumor suppressor in leukemia. Ikaros activity is essential for normal hematopoiesis and immune development and is expressed at high levels in most hematopoietic cells. Deletion of IKZF1 leads to the downregulation and upregulation of many important genes and is a predictor of poor outcomes in leukemia. We hypothesize that upregulation of glutaminase in cancer cells with IKZF1 deletion may be a mechanism whereby high-risk leukemias convey chemotherapy resistance. Conversely, Ikaros may help keep healthy hematopoietic cells in-check by preventing over-expression of glutaminase.

To test this hypothesis, we exposed two lines of B-ALL cells to the allosteric and selective glutaminase inhibitor BPTES. One cell line had IKZF1 intact (Nalm-6 scramble) and one had IKZF1 deleted via a CRISPR knockout (Nalm-6 IK KO). Treatments were done in triplicate with an exposure time of 72 hours. WST-1 viability assay was used to obtain an IC50 value for each cell line. Leukemia cells with IKZF1 knocked out had a two-fold higher IC50 than cells with IKZF1 intact. This indicates that IKZF1 deletion may convey chemotherapy resistance by upregulating glutaminase and implies that strategies targeting glutaminase may improve treatment outcomes in high-risk leukemia patients.