Heterogenous response of B lymphocytes to transforming growth factor‐beta in B‐cell chronic lymphocytic leukaemia: correlation with the expression of TGF‐β receptors

Abstract

Summary.We investigated the potential role of transforming growth factor-beta (TGF-b) on spontaneous and cytokineinduced proliferation of B-cell chronic lymphocytic leukaemia (B-CLL) cells in vitro. Purified B lymphocytes from 21 B-CLL patients were cultured for 5 d in the presence of medium alone, IL-2 and/or IL-10, in the presence or absence of TGF-b, and proliferation was measured by 3 H-thymidine incorporation. TGF-b inhibited B-cell proliferation in the majority of patients (15/21) but no inhibition was detected in 6/21 patients whatever the type of stimulant used. Addition of neutralizing antibodies to TGF-b increased spontaneous and cytokine-induced proliferation; this effect was dose dependent and specific because addition of an irrelevant chicken IgG had no effect on B-CLL proliferation. In resistant patients, neutralizing antibodies to TGF-b did not increase the proliferation. The expression of TGF-b receptors on B-CLL cells was significantly lower than the one observed on normal CD5 þ B lymphocytes for which the sensitivity to TGF-b inhibition was more marked than in CLL. In addition, we found a strong correlation between the response of leukaemic B cells to TGF-b inhibitory action and the expression of TGF-b receptors on these cells. In summary, TGF-b appears to function in CLL as a negative regulator of B lymphocytes but loss of responsiveness to this factor accompanied by a decrease of TGF-b receptor expression, might provide a selective advantage to B-CLL lymphocytes.

The effect of FK506 on transforming growth factor signaling and apoptosis in chronic lymphocytic leukemia B cells

“…31 Taken together, these findings suggest that FK506 induced activation of the TGF-β signal transduction pathway. In accordance with several reports suggesting that loss of response to TGF-β might provide a selective advantage to CLL B lymphocytes and contribute to the expansion of neoplastic clone, [8][9][10] our study showed an association between response to TGF-β and a LDT greater than 12 months, suggesting that the cytokine inhibited tumor cell growth. Therefore, rescue of TGF-β response in CLL by FK506 could represent a breakthrough in the treatment of this common hematologic malignancy.…”

“…2,4 Several lines of evidence support the view that the loss of sensitivity to TGF-β promotes leukemic transformation [5][6][7] and contributes to the clinical and biological progression of chronic lymphocytic leukemia (CLL). [8][9][10] This hematologic malignancy is a slowly progressing leukemia characterized by the gradual expansion of morphologically small, functionally inactive clonal B cells due to defective apoptosis. 11 TGF -β signals to the nucleus by binding to a specific pair of membrane receptors, type I (TGFBR1) and type II (TGFBR2), which contain a cytoplasmic serinethreonine kinase domain.…”

“…16 Identification of molecules able to restore the TGF-β response in B-CLL can have important implications in the treatment of this disease. [8][9][10] A network of regulatory inputs controls the TGF-β signaling pathway. 2 A recent study of fibroblasts from FK506 binding protein (FKBP) 12-knockout mice showed that the TGF-β pathway is overactive in cells lacking this protein.…”

“…18 The increased expression of FKBP12, that we found in some cases (data not shown) may, therefore, be one of the reasons for a lack of or no response to TGF-β. Reduced expression of TGFBR1 has been found by several authors in CLL [8][9][10] and suggested as a cause of insensitivity to TGF-β. It is feasible that in a condition of low receptor level, even normal levels of FKBP12 may be inhibitory and, possibly, the signal might be enhanced by FK506 also in these cases.…”

Disruption of Smad5 gene leads to enhanced proliferation of high-proliferative potential precursors during embryonic hematopoiesis

“…For instance, abnormalities in the expression of TGF-␤ receptors have been described in proliferative syndromes including both early myeloid 43,44 and lymphocytic leukemia. 45,46 Likewise, either Smad mutations or Smad functional inactivation have also been associated with malignant transformation. Chimeric transcription factors, such as AML1/Evi-1 and AML1/ETO resulting from t(3;21) and t(8;21) chromosomal translocations in chronic and acute myelogenous leukemia, have been documented to block TGF-␤ signaling by repression of Smad3 activity.…”