Elevated eIF4E is therapeutic target in Myeloma

eIF4E is the key regulator of protein translation and critical for translation. The oncogenic potential of tumorigenesis which is highly contingent on cap-dependent eIF4E also arises from the critical role in the nuclear export and cytosolic translation of oncogenic transcripts. Inhibition of Exportin1 (XPO1) which is the major nuclear export protein for eIF4E-bound oncoprotein-mRNAs results in decreased tumor cell growth in vitro and vivo suggesting that eIF4E is critical in multiple myeloma (MM). Indeed we found that eIF4E is overexpressed in myeloma cell lines and primary myeloma cells compared to normal plasma cells. While stable overexpression of eIF4E in MM cells significantly increases tumorigenesis, knockdown of eIF4E impairs MM tumor progression in human xenograft mice model. Using a tet-on inducible eIF4E-knockdown system, eIF4E-downregulation, blocks MM tumor growth in vivo correlating with decreased eIF4E expression. Further overexpression and knockdown of eIF4E revealed that eIF4E regulates translation of mRNAs with highly complex 5'-untranslated regions such as c-MYC and C/EBPβ and subsequently proliferation in MM cells, but not in non-malignant bone marrow stromal cells. Since many transcription factors that are critical for MM proliferation exhibit a higher dependency on protein translation, eIF4E is an ideal and selective tool to target MM cell growth.

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