Aberrant responses of human lymphocytic neoplasms to cytokine regulation.

Studies in this laboratory have recently focused on two hemic neoplasms: B cell chronic lymphocytic leukemia (B-CLL) and a T cell disorder, Sézary syndrome. These tumors do not have consistent cytogenetic or molecular genetic alterations, and so we have concentrated on their response to and production of various regulatory cytokines. Although B-CLL cells show variable proliferative responses when exposed to transforming growth factor beta (TGF beta), these cells have consistently shown resistance to the pro-apoptotic effects of this cytokine. Also, interleukin 4 (IL4), IL5, and interferon-gamma (IFN gamma) all show a consistently increased protective effect against apoptosis in B-CLL cells as compared to normal human B cells. Thus, a defect in apoptosis appears to be an important factor in the pathogenesis of CLL. By contrast, the neoplastic T cells of Sézary syndrome show a consistent resistance to the antiproliferative effects of TGF beta, suggesting that aberrant proliferation is more important than apoptosis in this disorder. In both neoplasms, we have shown that the defective responses to cytokines are in some instances related to alterations in receptor expression, but this has not been true in all circumstances, and other stages in the signaling pathways are being investigated. As we define more precisely the specific defects that contribute to the clonal expansion of these neoplasms, the findings may ultimately lead to improved clinical control of these disorders.