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Blood, 15 July 2007, Vol. 110, No. 2, pp. 743-751.
Prepublished online as a Blood First Edition Paper on April 3, 2007; DOI 10.1182/blood-2006-11-058446.
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Submitted November 16, 2006
Accepted March 31, 2007
NF- B2 mutation targets TRAF1 to induce lymphomagenesis
Baochun Zhang, Zhe Wang, Tai Li, Erdyni N Tsitsikov, and Han-Fei Ding*
Department of Biochemistry and Cancer Biology, University of Toledo Health Science Campus, Toledo, OH
Department of Pediatrics, Harvard Medical School, Boston, MA
* Corresponding author; email: han-fei.ding{at}utoledo.edu.
The NF- B2 gene is recurrently mutated in human lymphoid malignancies. However, a causal relationship between NF-B2 mutation and lymphomagenesis has not been established. It is also unclear how the mutation may lead to lymphoid malignancies. Here we report the generation of transgenic mice with targeted expression of p80HT, a lymphoma-associated NF-B2 mutant, in lymphocytes. The transgenic mice display a marked expansion of peripheral B cell population and develop predominantly B-cell lymphomas. p80HT expression has no apparent effect on the proliferation of B cells, but renders them specifically resistant to apoptosis induced by cytokine deprivation and mitogenic stimulation. Lymphocytes and lymphoma cells from p80HT mice express high levels of TRAF1, an anti-apoptotic protein also implicated in lymphoid malignancies. p80HT binds the TRAF1 promoter in vivo and activates TRAF1 transcription. Moreover, TRAF1 knockdown abrogates the anti-apoptotic activity of p80HT and TRAF1 deficiency reestablishes B cell homeostasis in p80HT mice. These findings demonstrate NF-B2 mutation as an oncogenic event in vivo and suggest a molecular pathway for TRAF1 activation in the pathogenesis of lymphomas.
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