Interferon‐γ arrests proliferation and causes apoptosis in stromal cell/interleukin‐7‐dependent normal murine pre‐B cell lines and clones in vitro, but does not induce differentiation to surface immunoglobulin‐positive B cells

Normal pre‐B cells from fetal liver or bone marrow of the mouse proliferate for long periods of time in tissue culture on stromal cells in the presence of interleukin‐7 (IL‐7). Their IgH loci are partly in germ‐line, partly in DHJH‐rearranged configuration, while their light chain loci are in germ‐line configuration. They express the pre‐B cell‐specific genes VpreB and λ5. Proliferation of these pre‐B cells is inhibited by interferon (IFN)‐γ, with half‐maximal inhibition at concentrations between 0.1 and 1 unit/ml. Normal pre‐B cells exposed to IFN‐γ die by apoptosis, as is evidenced by the disintegration of pre‐B cell DNA into oligonucleosomal multimers of 180‐200 bp. While the proliferation of pre‐B cells from Eμ‐bcl‐2 transgenic (tg) mice is inhibited by IFN‐γ, these cells do not die by apoptosis. IFN‐γ does not induce differentiation to more mature B lineage cells. In the absence of IL‐7 normal pre‐B cells differentiate to VHDHJH/VLJL‐rearranged, surface immunoglobulin‐positive B cells expressing the a chain of the IL‐2 receptor. They also down‐regulate the expression of VpreB and X.5, and lose the capacity to proliferate on stromal cells in the presence of IL‐7. In contrast, both normal and Eμ‐bcl‐2 tg pre‐B cells exposed to IFN‐γ in the presence of stromal cells and IL‐7 fail to differentiate, i.e. do not express surface immunoglobulin, retain expression of VpreB and λ5, do not express the α chain of the IL‐2 receptor, and retain the capacity to proliferate on stromal cells in the presence of IL‐7, once IFN‐γ is removed. The potential usefulness of a treatment of acute lymphocytic leukemia of the B cell lineage (pre B‐ALL) with IFN‐γ is discussed.