LB-47

Glucocorticoids (GC) have pronounced effects on metabolism, differentiation, proliferation and cell survival. In certain lymphocytes and lymphocyte-related malignancies, GC inhibit proliferation and induce apoptosis. This has led to their extensive use in the therapy of malignant lymphoproliferative disorders. Our lab has addressed the molecular basis of the anti-leukemic GC effects by a comparative gene expression profiling strategy using 13 ALL-children and other biological systems of GC-sensitivity and resistance. This study has provided a list of GC-regulated candidate genes, among which 6-phosphofructo-2-kinase,2,6-biphosphatase (PFKFB2), key enzyme of glucose metabolism, is the most frequently regulated gene in the ALL-children.

Maker and breaker of fructose-2,6-bisphosphate, the gene encodes two splice variant , which are differentially regulated in CCRF-CEM cell lines, our model of study.

To test the possible involvement of these proteins in GC-dependent cell death we generated lentiviral-constructs for conditional expression of PFKFB2 proteins and established several stable subclones of the human ALL cell line with tetracycline-regulated expression of the two PFKFB2 variants. Functional analyses showed a different role of the two variants in mediating GC-induced cell death.

The data suggest that deregulation of glucose metabolism by GC may contribute to GC-induced cell death in lymphoblastic leukemia cells (with potential therapeutical implications).

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA