Contribution of Amino Acid Metabolism to Hematologic Malignancies

Tumor cells rewire metabolic pathways to meet the high metabolic demands of proliferation, frequently developing auxotrophy to specific amino acid(s) (AAs) required to satisfy protein biosynthesis. Thus specific metabolic inhibitors or AA-depleting enzymes have been developed and tested as cancer therapeutics. For example, depletion of asparagine by bacterial L-asparaginase (ASNase) has proven efficacious against hematologic malignancies, especially leukemia and lymphoma, by starving tumors lacking asparagine synthetase (ASNS). We and others have reported that the glutaminase (GLS) activity of ASNase is required for anticancer activity against ASNS-positive leukemia cell types in vitro.1 In vivo, we have found that durable response to ASNase in pre-clinical models of leukemia also requires glutaminase activity, even against ASNS-negative leukemia models; a glutaminase-deficient mutant of ASNase yielded subsequent leukemia recurrence. We speculate that the underlying anti-leukemia mechanism mediated by ASNase glutaminase activity involves a deeper depletion of asparagine within the tumor microenvironment, since ASNS in nearby cells (adipocytes, mesenchymal stromal cells, etc.) can use glutamine as a precursor for asparagine synthesis. Nevertheless, since L-glutamine depletion is thought to cause the significant side effects of ASNase, enzyme variants with reduced glutaminase coactivity are being developed and tested. Another viable therapeutic strategy involving glutamine star...
Source: Blood - Category: Hematology Authors: Tags: Metabolism and Hematologic Malignancies Source Type: research