Abstract
High throughput DNA microarray has made it possible to outline genes whose expression in malignant plasma cells is associated with short overall survival of patients with Multiple Myeloma (MM). A further step is to elucidate the mechanisms encoded by these genes yielding to drug resistance and/or patients’ short survival. We focus here on the biological role of the DEP (for Disheveled, EGL-10, Pleckstrin) domain contained protein 1A (DEPDC1A), a poorly known protein encoded by DEPDC1A gene, whose high expression in malignant plasma cells is associated with short survival of patients. Using conditional lentiviral vector delivery of DEPDC1A shRNA, we report that DEPDC1A knockdown delayed the growth of human myeloma cell lines (HMCLs), with a block in G2 phase of the cell cycle, p53 phosphorylation and stabilization, and p21Cip1 accumulation. DEPDC1A knockdown also resulted in increased expression of mature plasma cell markers, including CXCR4, IL6-R and CD38. Thus DEPDC1A could contribute to the plasmablast features of MMCs found in some patients with adverse prognosis, blocking the differentiation of malignant plasma cells and promoting cell cycle.
Highlights
Multiple myeloma (MM) is a heterogeneous clonal plasma-cell disorder in terms of molecular abnormalities, proliferation, and differentiation
We report here that DEPDC1A gene expression in myeloma cells (MMCs) of previously-untreated patients with MM is associated with adverse prognosis, and that DEPDC1A knockdown induces growth retardation and overexpression of genes coding for mature plasma cell markers in multiple myeloma cell lines
DEPDC1A gene expression was significantly increased (P = .001) in MMCs of previously-untreated patients compared to normal bone marrow plasma cells (BMPCs) and in human myeloma cell lines (HMCLs) compared to primary MMCs (Figure 1A)
Summary
Multiple myeloma (MM) is a heterogeneous clonal plasma-cell disorder in terms of molecular abnormalities, proliferation, and differentiation. Numerous genes whose expressions in MMCs are associated with adverse or good prognosis have been identified and used to build gene expression-based prognostic scores [3,4,5,6,7,8,9]. Some of these genes encode for proteins involved in DNA replication, repair and recombination, as it is the case in other cancers [10,11,12,13]. A knockdown of DEPDC1A inhibited growth of bladder cancer cell line [21]
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