IL-7 sensitizes human pre-B cells but not pro-B cells to Fas/APO-1 (CD95)-mediated apoptosis

Abstract

SUMMARYHomeostasis of human B cell development is maintained by a complex network of cytoplasmic and surface expressed molecules. Abnormalities in this process may result in the expansion of malignant B cell precursors in B lineage acute lymphoblastic leukaemia (ALL). ALL cells share surface antigens with normal early precursor B cells. We have studied here the role of Fas/APO-1 (CD95) antigen on leukaemic precursor B cell line growth and survival, and the modulation of its effects by signals involved in normal early B cell development. Four ALL cell lines representative of the early steps of B cell differentiation are shown to express surface Fas/APO-1 (CD95) antigen and to undergo apoptosis in the presence of anti-Fas cross-linking antibodies. This effect is strongly enhanced when pre-B, but not pro-B cells, are pretreated with IL-7 but not with IL-2, IL-3, IL-4 or IL-10. Furthermore, pre-B cell death induced by anti-Fas antibodies in combination with IL-7 is increased upon pre-B receptor but not CD19 cross-linking. Bcl-2 and Bax protein expression is not influenced by IL-7 or pre-BR stimulation in either pro-B or pre-B cell lines. These results indicate that signals involved in normal early B cell development can modulate the Fas (CD95)-mediated apoptosis of leukaemic precursor B cells.

Interaction of interleukin-7 and interleukin-3 with the CXCL12-induced proliferation of B-cell progenitor acute lymphoblastic leukemia

“…The reasons for the latter are unclear but IL-7 and IL-3 have been reported to induce differentiation and apoptosis in a subpopulation of ALL cells. 35,40 Synergistic interactions between CXCL12 and Flt-3 ligand, granulocyte-macrophage colony-stimulating factor, stem cell factor and thrombopoietin have been observed in normal and leukemic myeloid progenitors cultured in the absence of stroma, resulting in enhanced survival, chemotaxis and proliferation. 21,41 In these studies CXCL12-enhanced responses to cytokines were associated with augmented signaling through ERK/MEK and PI-3K/AKT pathways, although the causative role of this was not always confirmed.…”

Inflammatory neutrophils retain susceptibility to apoptosis mediated via the Fas death receptor

“…Cells expressing equivalent levels of cell-surface Fas may differ in susceptibility to Fas-mediated death [10], and this susceptibility may be altered within a cell type, e.g., by stimulation of cytokine receptors [34][35][36]. We therefore examined the induction of apoptosis by Fas ligation in inflammatory compared with peripheral blood neutrophils, and the suppression of this death by co-incubation with a neutrophil survival factor.…”

TGF‐β1 modulates Fas (APO‐1/CD95)‐mediated apoptosis of human pre‐B cell lines

“…Fas receptor depend on the state of cell activation and, in particular, on the costimuli provided to the cells on which Fas receptor has been engaged [10][11][12][13][14]. Fas is involved in the homeostasis of the immune system, mainly by inducing cell death of activated B and T lymphocytes.…”

“…We have previously shown that programmed cell death of human pre-B cell lines can be triggered by crosslinking of membrane Fas protein and that IL-7 enhances Fas-induced apoptosis of pre-B but not pro-B cell lines [14]. In addition, pre-B cell receptor (pre-BCR) ligation significantly potentiates IL-7 effects on Fas-triggered pre-B cell death.…”