Loss-of-function mutations in genes encoding the signaling protein tumor necrosis factor receptor-associated factor 3 (TRAF3) are commonly found in human B-cell malignancies, especially multiple myeloma and B-cell lymphoma (BCL).
Furthermore, frequent homozygous deletions of genes playing important role in myeloma biology such as TRAF3, BIRC1/BIRC2, RB1, or CDKN2C were observed.
In vitro anti-tumor activities of AD 198 and PEP005 were determined using TRAF3-/- mouse B lymphoma and human patient-derived MM cell lines as model systems.
Single nucleotide polymorphisms in the TRAF3rs12147254 A allele and a specific haplotype 1 of TRAF3 [GAACAG] are associated with a decreased risk of multiple myeloma (odds ratio 0.709, P<0.001, and odds ratio 0.543, P<0.0001), while TRAF3 haplotype 4 [GGACAG] was associated with an increased risk of development of multiple myeloma (odds ratio 2.099, P=0.001).
Second, we confirm the critical role of TRAF2 in regulating NIK degradation, whereas TRAF3 enhances but is not essential for cIAP1/2-mediated proteasomal degradation of NIK in MM.