Myc suppression of Nfkb2 accelerates lymphomagenesis.
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-kappaB, transcription factors that control the immune response, cell survival, and transformation, and that are frequently altered in cancer. The Rel/NF-kappaB family member NFKB2 is altered by chromosomal translocations or deletions in lymphoid malignancies and deletion of the C-terminal ankyrin domain of NF-kappaB2 augments lymphocyte proliferation.


METHODS
Precancerous Emicro-Myc-transgenic B cells, Emicro-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 Emicro-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 Emicro-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-kappaB pathway.
Keller
Ulrich
U
III. Medical Department, Technische Universität München, Munich, Germany. ulrich.keller@lrz.tum.de
Huber
Jürgen
J
Nilsson
Jonas A
JA
Fallahi
Mohammad
M
Hall
Mark A
MA
Peschel
Christian
C
Cleveland
John L
JL
D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002051:Burkitt Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D052003:NF-kappa B p52 Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection
C489427:MYC protein, human; C489428:Myc protein, mouse; D052003:NF-kappa B p52 Subunit; C498206:NFKB2 protein, human; C498207:Nfkb2 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger