The intensity of expression of the chemokine receptor CCR5 is involved in in vitro cell infectability by human immunodeficiency virus (HIV)-1 R5 isolates. Because CCR5 expression varies among individuals, the hypothesis that this expression could determine virus load in HIV-1-infected persons was tested. The mean number of CCR5 molecules per cell was measured on peripheral blood CD4+ T lymphocytes (CCR5 density) from HIV-1-infected, asymptomatic, nontreated adults. There was a strong correlation between HIV RNA plasma level and CCR5 density (P=.009) that was independent of cell activation and was not due to an HIV-induced CCR5 up-regulation. These data are compatible with the hypothesis that CCR5 density is a key factor governing cell infectability and in vivo virus production and explain the protective effect of the Delta32CCR5 deletion, which results in low CCR5 expression. CCR5 density might be of critical predictive value in HIV infection.

Interleukin-6 (IL-6) is a major survival factor for malignant plasma cells involved in multiple myeloma. Using an RNase protection assay, we looked for gene expression of 10 anti- and proapoptotic Bcl-2-family proteins in 12 IL-6-dependent human myeloma cell lines (HMCL). A high Mcl-1 gene expression was found in all HMCLs and the other genes were variably expressed. Out of the 10 Bcl-2-family members, only the Mcl-1 gene was regulated by IL-6. Upon starvation of IL-6, Mcl-1 gene expression decreased in association with myeloma cell apoptosis and was upregulated after adding IL-6 again in association with myeloma cell survival. A constitutive Mcl-1 expression was induced with an Mcl-1-GFP retrovirus in two IL-6-dependent HMCLs. The Mcl-1 HMCLs have a marked reduced apoptosis upon IL-6 starvation compared to HMCLs transduced with control GFP retrovirus and may grow without adding IL-6. These data emphasize the major role of Mcl-1 antiapoptotic protein in the IL-6-induced survival of human myeloma cells.

In multiple myeloma (MM), the growth of primary plasma cells depends not only on interleukin-6 (IL-6), but also on additional unidentified signals delivered by the bone marrow environment. Using Atlas complementary DNA (cDNA) arrays comprising 268 genes coding for intercellular signaling molecules, this study identified genes that are overexpressed in myeloma cells compared to autologous B-lymphoblastoid cell lines. These genes encode the oncogenic Tyro3 tyrosine kinase receptor, the heparin-binding epidermal growth factor-like growth factor (HB-EGF) that is an epithelial autocrine tumor growth factor, the thrombin receptor (TR) that is linked to HB-EGF and syndecan-1 processing and to cell invasion, chemokine receptors CCR1 and CCR2, the Wnt pathway actor Frizzled-related protein (FRZB), and the Notch receptor ligand Jagged 2. These data, obtained with the Atlas cDNA array, were confirmed by reverse transcriptase-polymerase chain reaction or protein analysis or both. Furthermore, Tyro3, HB-EGF, TR, and FRZB gene expression was documented in purified primary malignant plasma cells from patients with plasma cell leukemia or MM. HB-EGF and FRZB were poorly expressed in purified polyclonal plasma cells. Finally, HB-EGF was proved to be an essential autocrine growth factor for the XG-1 myeloma cells. This study shows the po- IntroductionTumor development involves multiple mechanisms that lead to an increase in the survival of tumor cells and a deregulation of the cell cycle. Specifically, cell-to-cell growth signaling is likely to operate between tumor cells and their neighboring stromal cells. 1 In multiple myeloma (MM), the tight interactions between malignant plasma cells and their medullar environment exemplify this oncogenic process. As recently reported, myeloma cells produce the angiogenic growth factors, vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2), which may promote the neovascularization of the bone marrow observed as the disease activity increases. [2][3][4] Malignant plasma cells express adhesion molecules such as VLA4 and CD44, whose interactions with stromal cells and the extracellular matrix sustain MM cell survival. [5][6][7] Partly by producing interleukin-1 (IL-1), MM cells induce bone marrow stromal cells to synthesize IL-6, a major cytokine in MM biology. [8][9][10][11] However, purified MM cells cannot be rescued, even by IL-6, and require the presence of stromal cells for in vitro survival. [12][13][14][15] Thus, in the chronic phase of the disease, some molecules produced by stromal cells are critical, combined with IL-6, to promoting MM cell survival and proliferation. Growth factors able to bind heparan sulfate, such as FGFs, could be candidate molecules. Indeed, translocations involving the FGF receptor 3 are found in MM cells from patients with active disease and can confer an increase in the response of MM cells to IL-6 in vitro. 16,17 Moreover, MM cells are the only cells in the bone marrow that express syndecan-1, a heparan sulfate proteoglycan that i...

No abstract