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Open Access Research article

Myc suppression of Nfkb2 accelerates lymphomagenesis

Ulrich Keller12*, Jürgen Huber13, Jonas A Nilsson24, Mohammad Fallahi5, Mark A Hall25, Christian Peschel1 and John L Cleveland25

Author Affiliations

1 III. Medical Department, Technische Universität München, Munich, Germany

2 Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

3 Department of Anesthesiology, Technische Universität München, Munich, Germany

4 Department of Molecular Biology, Umeå University, Umeå, Sweden

5 Department of Cancer Biology, The Scripps Research Institute, Scripps Florida, Jupiter, Florida, USA

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BMC Cancer 2010, 10:348  doi:10.1186/1471-2407-10-348

Published: 2 July 2010

Abstract

Background

Deregulated c-Myc expression is a hallmark of several human cancers where it promotes proliferation and an aggressive tumour phenotype. Myc overexpression is associated with reduced activity of Rel/NF-κB, transcription factors that control the immune response, cell survival, and transformation, and that are frequently altered in cancer. The Rel/NF-κB family member NFKB2 is altered by chromosomal translocations or deletions in lymphoid malignancies and deletion of the C-terminal ankyrin domain of NF-κB2 augments lymphocyte proliferation.

Methods

Precancerous Eμ-Myc-transgenic B cells, Eμ-Myc lymphomas and human Burkitt lymphoma samples were assessed for Nfkb2 expression. The contribution of Nfkb2 to Myc-driven apoptosis, proliferation, and lymphomagenesis was tested genetically in vivo.

Results

Here we report that the Myc oncoprotein suppresses Nfkb2 expression in vitro in primary mouse fibroblasts and B cells, and in vivo in the Eμ-Myc transgenic mouse model of human Burkitt lymphoma (BL). NFKB2 suppression by Myc was also confirmed in primary human BL. Promoter-reporter assays indicate that Myc-mediated suppression of Nfkb2 occurs at the level of transcription. The contribution of Nfkb2 to Myc-driven lymphomagenesis was tested in vivo, where Nfkb2 loss was shown to accelerate lymphoma development in Eμ-Myc transgenic mice, by impairing Myc's apoptotic response.

Conclusions

Nfkb2 is suppressed by c-Myc and harnesses Myc-driven lymphomagenesis. These data thus link Myc-driven lymphomagenesis to the non-canonical NF-κB pathway.