Recent therapeutic advances have made the treatment of multiple myeloma both more complex and more costly. In particular, the median survival of patients with multiple myeloma has been markedly prolonged through the use of targeted drugs such as proteasome inhibitors and immune modulators.
IntroductionMultiple myeloma (MM) is an incurable plasma cell disorder. It is caused by the growth of a malignant plasma cell clone in the bone marrow (BM), leading to severe clinical symptoms such as lytic bone lesions, impaired hematopoiesis, and renal insufficiency. 1 MM is believed to evolve from a post-germinal center B cell through a multistep neoplastic transformation process culminating in oncogenic deregulation of growth and survival. 2,3 This process involves acquired genetic alterations, such as translocations between Ig enhancers and proto-oncogenes, as well as the interaction between tumor cells and their microenvironment in the BM. 4,5 Although most patients with MM initially respond to therapy, the disease usually recurs and progresses even under therapeutic intervention. Thus, the development of drug resistance during disease progression is considered a hallmark of MM. 6 However, better insight into the molecular mechanisms underlying disease progression and drug resistance in MM is needed to prevent or attenuate this development.The Y-box binding protein YB-1 belongs to a superfamily of cold-shock domain proteins that are highly conserved during evolution. 7 Eukaryotic Y-box proteins are involved in a wide variety of cellular functions, such as regulation of DNA transcription and repair and translational control of protein synthesis. 8,9 In particular, overexpression of YB-1 was found in fast proliferating cells, for example in interleukin-2 (IL-2)-stimulated T lymphocytes, or in hepatocytes of the regenerating zone after partial hepatectomy. 10 We previously reported that YB-1 is overexpressed in human breast cancer and is associated with a multidrug-resistant phenotype. 11 Increased levels of YB-1 expression have also been noted in other cancers, such as osteosarcoma, prostate cancer, pancreatic adenocarcinoma, ovarian carcinoma, colorectal carcinoma, and medulloblastoma. 12 Recently, we demonstrated that YB-1 expression provokes breast cancer in a YB-1-transgenic mouse model with a 100% penetrance. 13 Therefore, in addition to its role in drug resistance, YB-1 might act as a potent oncogene.Because the role of YB-1 in MM is virtually unknown, we have analyzed the expression of YB-1 in normal, premalignant, and malignant plasma cells in situ and investigated its contribution to survival and drug resistance in MM cells. Methods Cell cultureCulture conditions for the human IL-6-dependent MM cell lines INA-6 and MM.1s were previously described. 14,15 The MM cell lines used for analysis of YB-1 expression as shown in Figure S1 (available on the Blood website; see the Supplemental Materials link at the top of the online article) were also previously characterized. 16 BM stromal cells (BMSCs) from a patient with MM were derived from routine diagnostic BM aspirate after informed consent of the patient was obtained in accordance with the Declaration of The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. There...
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