NF-κB2 mutation targets TRAF1 to induce lymphomagenesis

Baochun Zhang, Zhe Wang, Tai Li, Erdyni N. Tsitsikov, Hanfei Ding

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

The NF-κB2 gene is recurrently mutated in human lymphoid malignancies. However, a causal relationship between NF-κB2 mutation and lymphomagenesis has not been established. It is also unclear how the mutation may lead to lymphoid malignancies. We report the generation of transgenic mice with targeted expression of p80HT, a lymphoma-associated NF-κB2 mutant, in lymphocytes. The transgenic mice display a marked expansion of peripheral B cell populations and develop predominantly small 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 antiapoptotic protein also implicated in lymphoid malignancies. p80HT binds the TRAF1 promoter in vivo and activates TRAF1 transcription. Moreover, TRAF1 knockdown abrogates the antiapoptotic activity of p80HT and TRAF1 deficiency reestablishes B cell homeostasis in p80HT mice. These findings demonstrate NF-κB2 mutation as an oncogenic event in vivo and suggest a molecular pathway for TRAF1 activation in the pathogenesis of lymphomas.

Original languageEnglish (US)
Pages (from-to)743-751
Number of pages9
JournalBlood
Volume110
Issue number2
DOIs
StatePublished - Jul 15 2007

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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