Metabolic control of p53 activation in T-ALL.

T cell acute lymphoblastic leukemia (T-ALL) is a childhood cancer that is treatable in many instances yet has a significant relapse rate that is difficult to cure.  A common cause for T-ALL is mutation of the gene, Notch, which regulates differentiation of hematopoietic cells, promotes cell survival, and stimulates cellular metabolism of glucose.  The ability of Notch to promote glucose metabolism is shared with many cancers and it has been long appreciated that cancer cells often have increased metabolism compared to their normal counterparts.  Importantly, this aspect of cancer biology may play an essential yet poorly explored role in survival of cancer cells.  In support of this notion, we have shown that increased glucose metabolism characteristic of T-ALL can inhibit the tumor suppressor, p53, and protect cells from death.  Here we hypothesize that cancers such as T-ALL develop a "metabolic addiction" to high rates of glucose metabolism and that learning how and why this occurs will inform rational strategies that interfere with cancer cell metabolism to activate p53 and cause cell death. We propose to: (1) examine the metabolism and metabolic dependencies of T-ALL cell lines in vitro, (2) determine mechanisms by which glucose metabolism inhibits p53, and (3) use mouse models that express cancer-promoting forms of Notch to determine how alteration of glucose metabolism affects p53 and T-ALL in vivo. Ultimately, this proposal will establish how this long-acknowledged yet underappreciated aspect of cancer biology may be modulated to provide innovative avenues in therapy of T-ALL and related cancers.