Interleukin (IL)-15 induces survival and proliferation of the growth factor-dependent acute myeloid leukemia M-07e through the IL-2 receptor β/γ

We have analyzed the effects of IL-15, a growth factor with IL-2-like properties produced by dendritic and stromal cells, on 3 GM-CSF/IL-3- dependent AML cell lines: M-07e, UT-7 and TF-I. M-07e cells proliferated in response to IL-15, while UT-7 and TF-I cells failed to respond. In addition, IL-15 supported long-term proliferation of M-07e cells, thus allowing selection of a subline (M-07SB), which displayed an enhanced sensitivity to IL-15. M-07e and M-07SB cells undergo apoptosis following 48-hr growth factor (GM-CSF or IL-15) starvation, as detected by cytofluorimetric analysis and DNA laddering. IL-15 (20 ng/ml) prevented apoptosis in both cell lines. M- 07e and M-07SB expressed IL-2Rβ, IL-2Rγ, Jak-1 and Jak-3 mRNA, while IL- 15Rα mRNA was undetectable. In contrast, IL-15Rα was expressed in UT-7 and TF-I cells, which lacked expression of IL-2Rβ mRNA and, in the case of UT- 7, also of Jak-3 mRNA. Accordingly, surface IL-2Rβ protein was identified only in M-07e and M-07SB cells, by indirect immunofluorescence, while no expression of IL-2Rα and IL- 15Rα was detected. Anti-IL-2Rβ antibodies (10 μg/ml) efficiently blocked (90% inhibition) the proliferation and the anti- apoptotic effect induced by IL-15, while anti-GM-CSFRα antibodies had no effect. Anti-IL-2Rγ antibodies were less efficient at proliferation inhibition but synergized with suboptimal concentrations of anti-IL-2Rβ antibodies. Our data suggest a role of IL-15 as an anti-apoptotic and mitogenic growth factor for a subset of myeloid leukemias expressing a functional I L-2Rβ/γ complex.