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Transcriptional Control and Signal Transduction

The eukaryotic translation initiation factor eIF4E is a direct transcriptional target of NF-κB and is aberrantly regulated in acute myeloid leukemia

Leukemia volume 27, pages 2047–2055 (2013)Cite this article

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Abstract

The eukaryotic translation initiation factor eIF4E is a potent oncogene elevated in many cancers, including the M4 and M5 subtypes of acute myeloid leukemia (AML). Although eIF4E RNA levels are elevated 3- to 10-fold in M4/M5 AML, the molecular underpinnings of this dysregulation were unknown. Here, we demonstrate that EIF4E is a direct transcriptional target of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) that is dysregulated preferentially in M4 and M5 AML. In primary hematopoietic cells and in cell lines, eIF4E levels are induced by NF-κB activating stimuli. Pharmacological or genetic inhibition of NF-κB represses this activation. The endogenous human EIF4E promoter recruits p65 and cRel to evolutionarily conserved κB sites in vitro and in vivo following NF-κB activation. Transcriptional activation is demonstrated by recruitment of p300 to the κB sites and phosphorylated Pol II to the coding region. In primary AML specimens, generally we observe that substantially more NF-κB complexes associate with eIF4E promoter elements in M4 and M5 AML specimens examined than in other subtypes or unstimulated normal primary hematopoietic cells. Consistently, genetic inhibition of NF-κB abrogates eIF4E RNA levels in this same population. These findings provide novel insights into the transcriptional control of eIF4E and a novel molecular basis for its dysregulation in at least a subset of M4/M5 AML specimens.

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Acknowledgements

These studies were supported by grants from the NIH (RO1 98571) and Leukemia and Lymphoma Society Translational Research Program to KLBB, the Ride to Conquer Cancer and the Canadian Foundation for Innovation to KKM. FH is supported by PhD studentships from the Fonds de la recherche en santé du Québec (FRSQ) and the Cole Foundation. MA is a fellow of the Leukemia and Lymphoma Society. KKM is a Chercheur Boursier of the FRSQ. KLBB holds a Canada Research Chair. The Institute for Research in Immunology and Cancer receives infrastructure support from the CIHR and FRSQ. Clinical specimens were collected and analyzed by the BCLQ of the Reseau de recherche sur le cancer of the FRSQ, which is affiliated with the Canadian Tumor Repository Network.

Author contributions

FH, MA and KLBB designed research. FH, MA, LV and THN performed research. FH, MA, BCK and KLBB analyzed the data. KKM and JH contributed valuable reagents. FH and KLBB wrote the manuscript.

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Author notes

  1. M Arguello

    Present address: 5Current address: Rosalind and Morris Goodman Cancer Research Center, McGill University, Montreal, Canada,

Authors and Affiliations

  1. Department of Pathology and Cell Biology, Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, Quebec, Canada

    F Hariri, M Arguello, L Volpon, B Culjkovic-Kraljacic & K L B Borden

  2. Department of Oncology, Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada

    T H Nielsen

  3. Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada

    J Hiscott & K K Mann

  4. Vaccine and Gene Therapy Institute of Florida, Port St Lucie, FL, USA

    J Hiscott

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Hariri, F., Arguello, M., Volpon, L. et al. The eukaryotic translation initiation factor eIF4E is a direct transcriptional target of NF-κB and is aberrantly regulated in acute myeloid leukemia. Leukemia 27, 2047–2055 (2013). https://doi.org/10.1038/leu.2013.73

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