INTERLEUKIN-6 PROMOTES MULTIPLE-MYELOMA CELL-GROWTH VIA PHOSPHORYLATION OF RETINOBLASTOMA PROTEIN

Interleukin-6 (IL-6) mediates autocrine and paracrine growth gf multip le myeloma (MM) cells and inhibits tumor cell apoptosis. Abnormalities of retinoblastoma protein (pRB) and mutations of RE gene have been re ported in up to 70% of MM patients and 80% of MM-derived cell lines. B ecause dephosphorylated (activated) pRB blocks transition from G1 to S phase of the cell cycle whereas phosphorylated (inactivated) pRB rele ases this growth arrest, we characterized the role of pRB in IL-6-medi ated MM cell growth. Both phosphorylated and dephosphorylated pRB were expressed in all serum-starved NIM patient cells and MM-derived cell lines, but pRB was predominantly in its phosphorylated form. In MM cel ls that proliferated in response to IL-6, exogenous IL-6 downregulated dephosphorylated pRB and decreased dephosphorylated pRB-E2F complexes . Importantly, culture of MM cells with RE antisense, but not RE sense , oligonucleotide (ODN) triggered IL-6 secretion and proliferation in MM cells; however, proliferation was only partially inhibited by neutr alizing anti-IL-6 monoclonal antibody (MoAb). In contrast to MM cells, normal splenic B cells express dephosphorylated pRB. Although CD40 li gand (CD40L) triggers a shift from dephosphorylated to phosphorylated pRB and proliferation of B cells, the addition of exogenous IL-6 to CD 40L-treated B cells does not alter either pRB or proliferation, as obs erved in MM cells. These results suggest that phosphorylated pRB is co nstitutively expressed in MM cells and that IL-6 further shifts pRB fr om its dephosphorylated to its phosphorylated form, thereby promoting MM cell growth via two mechanisms: by decreasing the amount of E2F bou nd by dephosphorylated pRB due to reduced dephosphorylated pRB, thereb y releasing growth arrest; and by upregulating IL-6 secretion by MM ce lls and related IL-6-mediated autocrine tumor cell growth. (C) 1996 by The American Society of Hematology.