Transforming growth factor β as endogenous growth inhibitor of chronic lymphocytic leukemia B cells

Abstract

Chronic lymphocytic leukemia (CLL) B cells are hyporesponsive or refractory to mitogens and growth factors in vitro. This study examined whether transforming growth factor β (TGF-β), a potent inhibitor of lymphocyte proliferation may play a role in the growth regulation of CLL B cells. CLL B cells from all donors treated expressed detectable TGF-β1 mRNA. In vitro release of TGF-β by unstimulated cultures, or cultures stimulated by antibody to cell surface immunoglobulin (anti-μ) plus phorbol 12- myristate 13-acetate (PMA) was higher in CLL than in normal B cells. High levels of TGF-β activity were also detected in plasma samples of CLL patients. The role of TGF-β in growth regulation of CLL B cells was tested in assays using different B cell activators. Purified neoplastic B cells from most CLL patients proliferated in response to anti-μ, or the combination of anti-μ plus PMA. Levels of CLL B cell proliferation were lower than observed in normal B cells. Some CLL were refractory to these stimuli. Antibody to CD40 induced proliferation of CLL B cells from all donors tested when presented on FcγRII (CDw32)-expressing L cells. Neutralizing antibodies to TGF-β increased CLL B cell proliferation in the absence or presence of additional stimuli. These effects were dose dependent and specific. Exogenous TGF-β completely inhibited CLL B cell proliferation induced by anti-μ, PMA, and anti-TGF-β. CLL B cell proliferation induced by anti-CD40 was reduced by exogenous TGF-β. However, even at high doses, TGF-β did not completely inhibit the anti-CD40 effect. In summary, TGF-β is overexpressed in CLL. CLL B cells are sensitive to TGF-β and this cytokine functions as an autocrine growth inhibitor accounting at least in part for reduced proliferative responses of these leukemic cells and for the slow progression of the malignant process in vivo.