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

K S Bommert; M Effenberger; E Leich; M Küspert; D Murphy; C Langer; R Moll; S Janz; A Mottok; S Weissbach; A Rosenwald; R Bargou; K Bommert

doi:10.1038/leu.2012.185

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

Journal article

Peer reviewed

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

K S Bommert, M Effenberger, E Leich, M Küspert, D Murphy, C Langer, R Moll, S Janz, A Mottok, S Weissbach, …

Leukemia, Vol.27(2), pp.441-450

02/2013

DOI: 10.1038/leu.2012.185

PMCID: PMC4047128

PMID: 22772059

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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.

oncogenic circuit

translational control

YBX1

Details

Title: Subtitle: The feed-forward loop between YB-1 and MYC is essential for multiple myeloma cell survival
Creators: K S Bommert - Division of Haematology and Medical Oncology, Department of Internal Medicine II, Comprehensive Cancer Centre Mainfranken, University Hospital Würzburg, Würzburg, Germany
M Effenberger - Division of Haematology and Medical Oncology, Department of Internal Medicine II, Comprehensive Cancer Centre Mainfranken, University Hospital Würzburg, Würzburg, Germany
E Leich - Institute of Pathology, University of Würzburg, Würzburg, Germany
M Küspert - Theodor Boveri Institute, University of Würzburg, Würzburg, Germany
D Murphy - Theodor Boveri Institute, University of Würzburg, Würzburg, Germany
C Langer - Department of Internal Medicine III, University of Ulm, Ulm, Germany
R Moll - Institute of Pathology, University of Giessen and Marburg, Marburg, Germany
S Janz - Department of Pathology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA
A Mottok - Institute of Pathology, University of Würzburg, Würzburg, Germany
S Weissbach - Institute of Pathology, University of Würzburg, Würzburg, Germany
A Rosenwald - Institute of Pathology, University of Würzburg, Würzburg, Germany
R Bargou - Division of Haematology and Medical Oncology, Department of Internal Medicine II, Comprehensive Cancer Centre Mainfranken, University Hospital Würzburg, Würzburg, Germany
K Bommert - Division of Haematology and Medical Oncology, Department of Internal Medicine II, Comprehensive Cancer Centre Mainfranken, University Hospital Würzburg, Würzburg, Germany
Resource Type: Journal article
Publication Details: Leukemia, Vol.27(2), pp.441-450
DOI: 10.1038/leu.2012.185
PMID: 22772059
PMCID: PMC4047128
NLM abbreviation: Leukemia
ISSN: 0887-6924
eISSN: 1476-5551
Language: English
Date published: 02/2013
Academic Unit: Pathology
Record Identifier: 9984083207802771

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