Myc suppression of Nfkb2 accelerates lymphomagenesis

Ulrich Keller,John L Cleveland,Jonas A Nilsson,Mohammad Fallahi,Mark A Hall,Christian Peschel,Jürgen Huber

doi:10.1186/1471-2407-10-348

Abstract

BackgroundDeregulated 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.MethodsPrecancerous 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.ResultsHere 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.ConclusionsNfkb2 is suppressed by c-Myc and harnesses Myc-driven lymphomagenesis. These data thus link Myc-driven lymphomagenesis to the non-canonical NF-κB pathway.

Highlights

Introduction to Nuclear factor (NF)κB: players, pathways, perspectives.Oncogene 2006, 25(51):6680-6684. 2
The Rel/NF-κB pathway is suppressed in Myc-induced lymphomas In the Eμ-Myc model of human B cell lymphoma disease progression is characterized by a pre-neoplastic state in which high proliferative rates of Eμ-Myc B cells are offset by high levels of apoptosis, which is disabled during progression to the malignant state [24,27]
The Rel/NFκB pathway is suppressed in Myc-transgenic precancerous B cells [22] and in human B lymphoma [21], yet the underlying targets in this response are not resolved

Summary

Introduction

Introduction to NFκB: players, pathways, perspectives.Oncogene 2006, 25(51):6680-6684. 2. Rayet B, Gelinas C: Aberrant rel/nfkb genes and activity in human cancer. 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. P100 NF-κB2 protein harbors a C-terminal ankyrin repeat domain that has intrinsic IκB activity, NF-κB promotes cell survival and proliferation, and alterations in this pathway, via chromosomal translocation or amplification, mutations, and deletions are common in cancer [7,8,9]. Loss of the C-terminal ankyrin domain of NF-κB2 in mice results in enlarged lymph nodes and augments lymphocyte proliferation [14]

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