Research in my laboratory has been focused on the molecular mechanisms underlying the pathogenesis of lymphomas. We are interested in the molecules that affect lymphocyte survival or apoptosis since failure of cells to die plays an important role in the pathogenesis of lymphocytic neoplasmas such as follicular lymphomas and chronic lymphocytic leukemias.

One of new molecules we have identified is PPAR gamma. PPAR gamma is a nuclear hormone receptor/transcriptional factor that requires ligand binding for activation. The receptor is a metabolic regulator that plays an important role in sensitizing tissues to the action of insulin and normalizing serum glucose and free fatty acids in type 2 diabetic patients. The receptor has also been implicated in the modulation of inflammatory responses and ligands of PPAR gamma have been found to induce apoptosis in lymphocytes. However, apoptosis induction may not depend on the receptor since high doses of PPAR gamma agonists are required for this process. Using cells containing or lacking PPAR gamma, we reported that PPAR gamma attenuates apoptosis induced by cytokine withdrawal in a murine lymphocytic cell line via a receptor dependent mechanism. PPAR gamma exerts this effect by enhancing ability of cells to maintain their mitochondrial membrane potential during cytokine deprivation. Recently, we demonstrate that activation of PPAR gamma also protects cells from serum starvation-induced apoptosis in human T lymphoma cell lines. We showed that the survival effect of PPAR gamma is mediated through its actions on cellular metabolic activities. In cytokine-deprived cells, PPAR gamma attenuates the decline in ATP level and suppresses accumulation of reactive oxygen species (ROS). Moreover, PPAR gamma regulates ROS through its coordinated transcriptional control of proteins and enzymes involved in ROS scavenge. Our studies identify cell survival promotion as a novel activity of PPAR gamma and suggest that PPAR gamma may contribute to the survival of these malignant cells.

The laboratory also works on several other translational research projects. We aim at utilizing information about molecular pathogenesis of hematologic malignancies for diagnosis, disease monitoring and therapeutic intervention. The lab has developed several new assays and is currently an active participant in an international collaborative project attempting to standardize the BCR-ABL qRT-PCR test for molecular monitoring of chronic myelogenous leukemia. Cutting-edge technologies such as DNA microarray, Laser Capture Microdissection, Real-Time PCR, RNAi and phospho-flow are employed for various studies.