ABERRANT RESPONSES OF HUMAN LYMPHOCYTIC NEOPLASMS TO CYTOKINE REGULATION

Studies in this laboratory have recently focused on two hemic neoplasm s: B cell chronic lymphocytic leukemia (B-CLL) and a T cell disorder, Sezary syndrome. These tumors do not have consistent cytogenetic or mo lecular genetic alterations, and so we have concentrated on their resp onse to and production of various regulatory cytokines. Although B-CLL cells show variable proliferative responses when exposed to transform ing growth factor beta (TGF beta), these cells have consistently shown resistance to the pro-apoptotic effects of this cytokine. Also, inter leukin 4 (IL4), IL5, and interferon-gamma (IFN gamma) all show a consi stently increased protective effect against apoptosis in B-CLL cells a s compared to normal human B cells. Thus, a defect in apoptosis appear s to be an important factor in the pathogenesis of CLL. By contrast, t he neoplastic T cells of Sezary 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 b oth 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 t he signaling pathways are being investigated. As we define more precis ely the specific defects that contribute to the clonal expansion of th ese neoplasms, the findings may ultimately lead to improved clinical c ontrol of these disorders.