Chronic lymphocytic leukemia (CLL) has the highest incidence among adults in western countries. Prognosis of CLL is highly variable but one of the biomarker zeta-chain-associated protein 70 (ZAP70) over expression is associated with aggressive disease with time to treatment being 2.6 years for ZAP70 expressing (ZAP70+) patients and 8 years for ZAP70 deficient (ZAP70-) patients. Thus ZAP70 may play a role in CLL progression. Metabolic reprograming plays a central role in cancer progression and is altered in CLL cells. However, the role of ZAP70 in metabolism in CLL cells is remains unclear. We found that ZAP70 binds to pyruvate kinase M2 (PKM2). PKM2 is key isoform of pyruvate kinase which is rate limiting enzyme of the glycolytic pathway and provides a metabolic advantage to tumour cells allowing for increased growth. Our results also indicated the PKM2 is expressed in CLL cells and binding to ZAP70 is not affected by glucose starvation or treatment with kinase inhibitors. Furthermore immunofluorescence microscopy revealed that ZAP-70 and PKM2 colocalize in CLL cells in the cytoplasm. In addition, we found ZAP70+ cells have increased rate of oxygen consumption from basal level determined by addition of inhibitor (Oligomycin A) and mitochondrial uncoupler (FCCP). Simultaneously ZAP70+ cells also have higher extracellular acidification rates. This indicates ZAP70+ CLL cells have increased mitochondrial respiratory capacity with high glycolytic rate. In addition, fluorometric analysis indicates ZAP70+ CLL cells have high glucose consumption rate towards production of lactate compared to ZAP70- CLL cells. Collectively, our data reveals a new function for ZAP70, which is to regulate the Warburg effect and may play a role in CLL progression and may identify new therapeutic targets.
Note: This abstract was not presented at the meeting.
Citation Format: Subhadip Das, RF Dielschneider, Elizabeth S. Henson, Spencer B. Gibson. ZAP70 alters metabolism in chronic lymphocytic leukemic cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5423. doi:10.1158/1538-7445.AM2017-5423