Multiple myeloma (MM) is characterized by accumulation and dissemination of malignant plasma cells (PCs) in the bone marrow (BM).It is generally believed that myeloma cells are dependent on growth factors for proliferation and survival.The observation that many cytokines have redundant effects on growth of MM cells, led us to hypothesize that the intracellular signals from cytokines converge and regulate transcription of a set of genes that are common targets for several growth factors.For future treatment, it may be futile to directly target the cytokines or their receptors because of redundancy in signaling but, if this hypothesis is correct, one could attack selected genes that are common downstream targets for all the cytokines.Gene expression profiling of 2 MM cell lines (OH-2 and IH-1) indicated that expression of PRL-3 was induced by several mitogenic cytokines.The PRL-3 gene codes for a dual specificity phosphatase, and there are several reports showing its importance in cancer cell invasion and migration, especially in colon cancer and several other carcinomas.Cytokine-driven PRL-3 expression could be shown in several myeloma cell lines at both the mRNA and protein levels.There was significantly higher expression of the PRL-3 gene in PCs from patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma (SMM),and myeloma than in PCs from healthy persons.Silencing of the PRL-3 gene by siRNA reduced cell migration in the MM cell line INA-6, but seemed to have no detectable effect on proliferation and cell-cycle phase distribution of the cells.However, a low-molecular inhibitor of PRL-3 attenuated proliferation and survival of MM cells and blocked cytokine-induced adhesion of MM cells to fibronectin.In conclusion, PRL-3 is a gene product specifically expressed in malignant plasma cells and may have a role in migration, adhesion and growth of these cells.