NF-κB2 mutation targets TRAF1 to induce lymphomagenesis

Abstract

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. 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 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-B2 mutation as an oncogenic event in vivo and suggest a molecular pathway for TRAF1 activation in the pathogenesis of lymphomas. ( IntroductionThe mammalian NF-B family consists of 5 structurally related proteins, including RelA, RelB, c-Rel, NF-B1 (p50 and its precursor p105), and NF-B2 (p52 and its precursor p100). The active forms of NF-B are dimers composed of various combinations of the family members, which bind a common DNA sequence motif known as the B site and regulate the expression of genes crucial to the development and functions of lymphocytes. NF-B activity is controlled by IB (inhibitor of B) proteins and the IB-like ankyrin-repeat domain in the C-terminal region of NF-B2 p100. IB proteins interact with NF-B dimers composed of NF-B1 p50 and RelA or c-Rel, and NF-B2 p100 is primarily associated with RelB. The interactions prevent NF-B dimers from translocating to the nucleus. On stimulation by certain cytokines, IBs and the C-terminal region of p100 are phosphorylated by IB kinase and degraded by the proteasome. The freed p50-RelA/c-Rel or resulting p52-RelB dimers then translocate to the nucleus and transactivate their target genes. 1 Constitutive NF-B activation plays an important role in tumorigenesis by promoting cell proliferation and survival. Several mechanisms have been identified by which activation of NF-B is uncoupled from its normal modes of regulation in cancer cells. Most of these mechanisms target IB kinase for activation of NF-B. 2,3 Sustained NF-B activation can also be caused by genetic alterations that affect the activity and expression of NF-B proteins. 4 The first gene of the family found to be mutated in human lymphoid malignancies is NF-B2. 5 Subsequent studies revealed that chromosomal rearrangements at the NF-B2 locus occur in a variety of B and T cell lymphoid malignancies. [6][7][8][9] A cardinal feature of these genetic alterations is the generation of C-terminally truncated NF-B2 mutants that lack various portions...

Matrix Metalloproteinase-9 gene induction by a truncated oncogenic NF-κB2 protein involves the recruitment of MLL1 and MLL2 H3K4 histone methyltransferase complexes

“…Although there is now experimental evidence for a key role of this chromosomal translocation in lymphomagenesis (Zhang et al, 2007), it remained unclear whether the loss of the inhibitory function of p100 and/or the overproduction of p52 is the underlying mechanism. There are several evidences for p52 being essential for the oncogenic potential of the truncated NF-kB2 proteins.…”

“…Mice with a homozygous deletion of the C-terminal ankyrin repeats of p100, which allows them to express p52 but not the inhibitory protein p100, suffered from gastric hyperplasia and also showed enlarged lymph nodes and increased proliferation of peripheral lymphocytes (Ishikawa et al, 1997). Interestingly, a transgenic mouse overexpressing a lymphoma-associated NF-kB2 mutant Hut-78 in lymphocytes developed small B-cell lymphomas, in part through the upregulation of the antiapoptotic protein TRAF1 (Zhang et al, 2007).…”

NF-κB and cancer—identifying targets and mechanisms

“…Activation of NF-κB (usually assessed by presence of nuclear RelA) has been observed in many cancers, including but not limited to breast cancer 14 , melanoma 15 , lung cancer 16 , colon cancer 17 , multiple myeloma 13 , pancreatic cancer 18 , esophageal adenocarcinoma 19 , and various types of leukemia 20-22 and lymphoma 23,24 . The presence of activated NF-κB in tumors does not, however, establish a causal link.…”

Mouse Models of Chronic Lymphocytic Leukemia

“…Interestingly, Zhang and coworkers (Zhang et al, 2007) have provided proof of the direct involvement of dysregulated NFB2 in the development of SLL/CLL. These authors developed transgenic mice expressing in lymphocytes p80HT, a lymphoma-associated NFB2 mutant (Kim et al, 2000).…”