Description of Research Expertise
Research in our laboratory is focused on the contribution of failure of normal growth regulatory controls to the development of hematologic malignancies. Alterations in the balance of apoptosis and proliferation may lead to chronic leukemic states such as B cell chronic lymphocytic leukemia (B-CLL). Consistent genetic defects have been difficult to identify in B-CLL; hence our focus has been on alterations in cytokine networks which may affect the cellular environment of the malignant clone. We showed that TGFbeta, a potent immunosuppressive cytokine which can induce apoptosis and inhibit proliferation, is overproduced in mice and humans with B- CLL, but the leukemic B cells fail to respond to the apoptotic signals provided by TGFbeta. This defect in TGFbeta responsiveness is not due to a lack of expression of TGF receptors, but appears to be a failure in the signal transduction pathway for this cytokine. In addition to TGFbeta, we have investigated the role of T cell produced cytokines (IL4 and IFNg) in regulating the apoptotic process in CLL B cells.
We found a predominance of IFNg producing T cells in these patients as compared to normals, and that the leukemic B cells express higher levels of IFNg receptors. Interestingly, this cytokine has an extremely anti-apoptotic effect on the B cells. Thus, the leukemic B cell is producing a cytokine that can cause potent immunosuppression (and apoptosis) of other cells while being itself resistant and appears to be overly responsive to the anti-apoptotic effects of IFNg. Taken together, these aberrations could contribute to the survival and expansion of the malignant B cell. Current investigations are focused on the role of other cytokines in the control of hematologic malignancies, using both human and murine models, with the intent of identifying potent targets for therapy.
The laboratory is also involved in the development of new flow cytometric applications for research and clinical use. This includes basic and translational studies on applications for monitoring receptor/ligand binding, multiparameter functional studies, minimal residual disease detection, stem cell isolation and identification, and transplantation monitoring.
Peter Nowell, M.D. Pathology
Bruce Rosengard, M.D , Surgery
Alain Rook, M.D., Dermatology