[HTML][HTML] Myc suppression of Nfkb2 accelerates lymphomagenesis

U Keller, J Huber, JA Nilsson, M Fallahi, MA Hall… - BMC cancer, 2010 - Springer
U Keller, J Huber, JA Nilsson, M Fallahi, MA Hall, C Peschel, JL Cleveland
BMC cancer, 2010Springer
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 …
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.
Springer