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Targeting the Translational Machinery in Multiple Myeloma
Shirong Li, PhD
University of Pittsburgh
Pittsburgh, Pennsylvania, USA

The translation initiation factor elF4E plays a central role in protein synthesis in eukaryotic cells. The overexpression and/or activation of elF4E have been associated with tumor formation and progression in human malignancies including leukemia, lymphoma, and cancers of the breast, colon, lung and prostate. A variety of novel therapeutics targeting this mechanism as a treatment for cancer is in development. However, in multiple myeloma, the role of elF4E in the pathogenesis and its feasability as therapeutic target is unknown. Our previous data showed the levels of elF4E are significantly elevated in multiple myeloma. Interestingly, we found that Immunomodulatory Derivatives of Thalidomide (IMiDs) negatively regulate elF4E and consequently suppress the expression of transcription factors such as C/EBPß, IRF4 and XBP1 which are essential for multiple myeloma cell survival. Furthermore, we found that the failure of down-regulating elF4E and C/EBPß by IMiDs is associated with drug resistance to IMiDs, indicating that elF4E machinery might be the critical mediator of drug resistance. Therefore, understanding the mechanisms that control protein synthesis is an exciting new research area in multiple myeloma with significant potential for developing innovative therapies. The goal of this study is to determine the role and regulation of elF4E and C/EBPß in multiple myeloma, and to provide new strategies and clues for optimal treatment for multiple myeloma therapy.

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