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IFN- Is a Survival Factor for Human Myeloma Cells and Reduces Dexamethasone-Induced Apoptosis¹

Martine Ferlin-Bezombes^*, Michel Jourdan^*, Janny Liautard^*, Jean Brochier^*, Jean-François Rossi and Bernard Klein^2,*,

^* Institut National de la Santé et de la Recherche Médicale, Unit 475, Service des Maladies du Sang B, Centre Hospitalier Universitaire Montpellier, and Unit for Cellular Therapy, Centre Hospitalier Universitaire Montpellier, Hôpital Saint Eloi, Montpellier, France

IFN- is used as a maintenance therapy in patients with multiple myeloma, but its benefit is a matter of controversy. In vitro studies show that IFN- can both stimulate and inhibit myeloma cell proliferation. We have tested the effect of IFN- on the survival of myeloma cell lines and primary plasma cells. IFN- significantly reduced the apoptosis induced by removal of IL-6 in four IL-6-dependent myeloma cell lines. It also reduced the level of apoptosis induced by dexamethasone in these cell lines as well as in purified primary myeloma cells from seven patients. IFN- promoted the survival of myeloma cells, which, following removal of IL-6, were blocked in G1 and died. However, unlike IL-6, IFN--treated cells remained mainly blocked in the G1 phase of the cycle. While the effects of IL-6 are mediated through stimulation of its gp130 receptor subunit, the IFN--induced survival of myeloma cells was independent of gp130 transducer activation (as demonstrated using a neutralizing anti-gp130 Ab). However, the signal transduction cascades activated by these two cytokines share at least some common elements, since stimulation with either IFN- or IL-6 resulted in STAT3 phosphorylation. These results indicate that IFN- promotes the survival, but not the proliferation, of myeloma cells, preventing the apoptosis induced by removal of IL-6 or addition of dexamethasone. This survival factor activity may explain the conflicting reports on the effects of IFN- on myeloma cell proliferation.

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