Ca2+ Release Activated Ca2+ (CRAC) Channels in Control of Leukemic Cell Metabolism and Leukemia Stem Cell Maintenance in T-ALL
T-cell acute lymphoblastic leukemia (T-ALL) is a white blood cell cancer in which tumor cells originating from the bone marrow spread using the bloodstream and invade peripheral organs. Advancement in treatment today allow 80-90% of the patients to recover. However, a significant percentage of them experience relapses. Relapses after successful remission were suggested to occur due to leukemic stem cells that survive the primary therapy and re-establish a harder to treat tumor. Some important studies now point out that therapy insensitive leukemic stem cells could be targeted based on their distinct way to utilize glucose. Leukemia stem cells were found to break down glucose in their mitochondria, the energy producing "power-plants" of cells, as opposed to regular leukemic cells, which utilize glucose in a less-efficient way.
Our preliminary data indicates that a druggable calcium channel, the so called CRAC channel, may be crucial for leukemia stem cells to maintain mitochondrial glucose breakdown. We found that genetic deletion of CRAC channels in leukemic cells prolongs the overall survival of mice with T-ALL. CRAC channel deficient leukemic cells die more frequently than wild-type leukemic cells resulting in reduced numbers of tumor cells and increased survival for mice with T-ALL. We found that leukemic cells lacking CRAC channels have difficulties to utilize genes required for mitochondrial glucose breakdown.
Here, we would like to test the idea that CRAC channels indeed support mitochondrial glucose breakdown in leukemia stem cells, and that using inhibitors against these channels may prevent relapses in pediatric T-ALL.