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Myeloma

The feed-forward loop between YB-1 and MYC is essential for multiple myeloma cell survival

Leukemia volume 27, pages 441–450 (2013)Cite this article

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Abstract

Y-box binding protein 1 (YB-1) functions as a translational regulator and has been suggested to elevate MYC mRNA translation via an internal ribosome entry segment (IRES) point mutation in multiple myeloma (MM). We show that YB-1-mediated translation of MYC mRNA occurs independently of the reported IRES mutation, as 87 MM patients (n=88) and all tested human MM cell lines (HMCLs) were negative for the mutation. We show for the first time that positive MYC staining predicts YB-1 co-expression in malignant plasma cells and YB-1/MYC co-expression increases from 30% in medullary to 70% in extramedullary MM. YB-1 knockdown in HMCLs reduced both MYC protein levels and MYC mRNA in the polysomal fraction, providing a mechanism by which YB-1 controls MYC translation. MYC transcription of YB-1 is demonstrated in HMCLs as MYC knockdown resulted in reduced YB-1 protein and mRNA levels. Furthermore, MYC activation in non-malignant mouse embryonic fibroblasts (MEFs) increased YB-1 mRNA, clearly indicating that MYC drives YB-1 transcription. Importantly, perturbation of the MYC/YB-1 oncogenic circuit leads to apoptosis in HMCLs. Here, we demonstrate that these two proteins co-regulate each other via combined transcriptional/translational activity establishing their pivotal role in MM cell survival. We therefore suggest that targeting the YB-1/mRNA interaction provides a new strategy for MM drug development.

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Acknowledgements

We would like to thank C Linden, Institute for Immunobiology, for cell sorting, M Göbel, IZKF Würzburg, for the Bioanalyzer runs; G Bornkamm for the P493-6 cell line; M Nikiforov and M Chatterjee for plasmids encoding shRNA against MYC and YB-1, respectively; and N Königl for technical assistance. This work was supported by the Deutsche Forschungsgemeinshaft (DFG, CRU 216 and SFB-TR 17), by the Interdisciplinary Centre for Clinical Research (IZKF) of Würzburg University and by the Multiple Myeloma Research Foundation (MMRF, USA).

AUTHOR CONTRIBUTIONS

KSB and KB designed, performed and analysed experiments, and contributed to writing the manuscript; RB reviewed the manuscript; ME designed, performed and analysed experiments in HMCLs, and contributed to the writing of the manuscript; EL, SW, ME and AR performed and analysed the IP experiments, EL contributed to the writing of the manuscript. MK and ME performed and analysed density gradient centrifugation. DM and ME performed and analysed the data on MEFs and carefully reviewed the manuscript; CL was responsible for the studies on the point mutation in the MYC IRES, and reviewed the manuscript; SJ provided transgenic mouse tissue samples and reviewed the manuscript. AM and AR stained and evaluated MM material, RM provided and evaluated extramedullary plasmacytomas.

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Author notes

  1. K S Bommert and M Effenberger: These two authors contributed equally to this work.

Authors and Affiliations

  1. Division of Haematology and Medical Oncology, Department of Internal Medicine II, Comprehensive Cancer Centre Mainfranken, University Hospital Würzburg, Würzburg, Germany

    K S Bommert, M Effenberger, R Bargou & K Bommert

  2. Institute of Pathology, University of Würzburg, Würzburg, Germany

    E Leich, A Mottok, S Weissbach & A Rosenwald

  3. Theodor Boveri Institute, University of Würzburg, Würzburg, Germany

    M Küspert & D Murphy

  4. Department of Internal Medicine III, University of Ulm, Ulm, Germany

    C Langer

  5. Institute of Pathology, University of Giessen and Marburg, Marburg, Germany

    R Moll

  6. Department of Pathology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA

    S Janz

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  1. K S Bommert
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Correspondence to K Bommert.

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Bommert, K., Effenberger, M., Leich, E. et al. The feed-forward loop between YB-1 and MYC is essential for multiple myeloma cell survival. Leukemia 27, 441–450 (2013). https://doi.org/10.1038/leu.2012.185

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