Excessive production of transforming growth factor-beta by bone marrow stromal cells in B-cell chronic lymphocytic leukemia inhibits growth of hematopoietic precursors and interleukin-6 production

Abstract

To explore the pathogenesis of marrow failure in B-cell type chronic lymphocytic leukemia (B-CLL), we have examined the production of interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage CSF (GM-CSF) by the adherent cell population of bone marrow (BM) derived from B-CLL patients and their capacity to support hematopoietic cell proliferation. Lipopolysaccharide-stimulated B-CLL stromal cells produced G-CSF and GM-CSF in amounts similar to normal stromal layers, whereas IL-6 production was significantly decreased. Using the blast-colony forming cell assay (BI-CFC) and the classical colony-forming unit granulocyte macrophage (CFU-GM) assay, we found that: (1) marrow stromal cells of B-CLL were able to support only 25% of the BI-CFC growth supported by normal marrow stromal cells; (2) this anomaly was partially corrected by the addition of exogenous IL-6; (3) the colony-stimulating activity (CSA) of the conditioned medium (CM) of B-CLL stromal cells was lower than that of normal CM; (4) that this was the result of the presence of an inhibitor rather that of a growth factor defect; (5) this inhibition could be abrogated by addition of anti-transforming growth factor-beta (TGF-beta) neutralizing antibody; (6) this antibody corrected the deficient colony supportive activity of the B-CLL stromal cells; (7) TGF-beta production by marrow stromal cells was significantly increased in CLL compared with normal; and (8) that this was not caused by the effect of the B- CLL lymphocytes on the stromal cells. It is concluded that this increased TGF-beta production in B-CLL is probably responsible for the decreased IL-6 production by stromal cells and for the inhibiting activity on hematopoietic precursors as well. We hypothesize that TGF- beta generated at a high level by B-CLL marrow stromal cells could play a major role in the pathophysiology of the BM failure seen in advanced stages of B-CLL.

Cytokines released in vitro by stromal cells from autologous bone marrow transplant patients with lymphoid malignancy

“…These results are in accordance with a study (18) which showed that, in normal human LTBMC, primitive progenitor cycling changes can be correlated with a decrease in TGFP even when stimulator production is declining. Our results are not consistent with an inhibitory effect of TGFP on hematopoiesis after ABMT, in contrast to bone marrow failures seen in advanced stages of B-cell chronic lymphocytic leukemia (28). In fact, TGFP could have bidirectional effects on the proliferation and differentiation of human hematopoietic progenitor cells.…”

“…The samples were obtained sequentially prior to BMT and 3 months after BMT for 10 patients, 1 yr after BMT for 7 patients and from 11 control patients without hematological disorders (9 patients with glioblastoma at the time of graft collection for ABMT and 2 patients undergoing cardiac surgery). The 12 test patients ranged in age from 31 to 50 yr (median=43) The 11 controls (5 females and 6 males) ranged in age from 28 to 61 yr (median=45) and did not receive any previous chemotherapy (control patients with glioblastoma showed identical number of marrow progenitors compared to controls without malignancy, data not shown).…”

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

“…These findings suggest that the loss of receptors or receptor function for TGF-b on B-CLL lymphocytes, but not on normal haemopoietic cells, may allow leukaemic cells to escape the growth inhibiting effect of TGF-b. The proliferative advantage that this situation could provide to the leukaemic cells over normal haemopoietic cells could be aggravated by another anomaly that we described earlier (Lagneaux et al, 1993), namely that stromal cells are producing more TGF-b in CLL patients than in normal subjects. This could, via the potent immunosuppresive effect of TGF-b, facilitate the expansion of leukaemia.…”

Biological and molecular characterization of PNH‐like lymphocytes emerging after Campath‐1H therapy

“…Compared with the CLL group, we found increased production of TGF‐β, a well‐known inhibitory cytokine. Excessive production of TGF‐β by bone marrow stromal cells has been hypothesized to be responsible for the inhibitory activity on haematopoietic precursors in CLL (Lagneaux et al , 1993). Given the inhibitory activity of TGF‐β, our results may suggest that elevated levels of this cytokine could contribute to alterations of the micro‐environment and synergize with the selective pressure of Campath‐1H, leading to expansion of pre‐existing PNH‐like lymphocytes (Rawstron et al , 1999).…”