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R. Burkhard et al.
DLBCLs.32,47 Furthermore, we linked the enhanced prolif- eration of TIRAP p.R81C B cells with an increased expres- sion of NF-kB target genes and genes involved in cell sur- vival and proliferation in PBMCs. In this context, it is important to stress that we determined the lymphocytes to account for more than 65% of cells in the PMBC sam- ples analyzed. In addition, TIRAP knockdown was paral- leled by a significant decrease in the gene expression sig- nature of the NF-kB pathway, particularly in PBMCs car- rying the p.R81C variant. In contrast, overexpression of TIRAP p.R81C increased NF-kB gene signature in vitro. Moreover, TIRAP p.R81C-expressing cells showed enhanced resistance to stress-induced apoptosis, indicat- ing that TIRAP p.R81C provides a survival advantage under those conditions.
Our data link TIRAP p.R81C variant/expression with increased B-cell proliferation as well as survival, and thus add TIRAP to the existing network of lymphoma risk genes that are associated with deregulated NF-kB signal- ing such as TNFAIP3, CD79A/B, MYD88 and CARD11. Interestingly, all these genes were unmutated in the lym- phomas of both sisters. Similar to patients expressing the oncogenic p.L265P MYD88 variant, patients with aberrant TIRAP signaling might benefit from IRAK4-selective kinase inhibitors.48
Diffuse large B-cell lymphoma is a polygenic disease with a complex pathogenesis. Therefore, additional alter- ations are required for the full malignant transformation of B-cells. Interestingly, all the family members investigated were found to have a homozygous germline loss of GSTT1, a reported risk factor for lymphomas (Online Supplementary Figure S7).18 One can hypothesize that the interplay of the germline TIRAP p.R81C variant and
GSTT1 loss coupled with additional genomic changes cul- minated in B-cell transformation in the investigated fami- ly. The identification of the TIRAP p.R81C variant in a family with mixed ethnic background, along with the demonstration of distinct targets of recurrent mutations in Chinese DLBCLs,49 might be an important additional aspect.
Overall, our findings revealed TIRAP p.R81C to be a potential lymphoma risk variant in a family of mixed eth- nic background. Our analysis complements the existing view on the different players of the NF-kB pathway cru- cially involved in DLBCL.
Acknowledgments
The authors would like to thank Magne Osteras and his team at Fasteris (Geneva, Switzerland) for their excellent technical assistance. The probe for the TNFAIP3 FISH analysis was a gift from Laura Pasqualucci and Riccardo Dalla-Favera (Institute for Cancer Genetics, Columbia University, New York, NY, USA). The determination of CIITA rearrangement by FISH was kindly performed by Laurence de Leval (Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland). We thank Lukas Mager, Deborah Krauer, Mario P. Tschan, Emilly Auma, Adrian F. Ochsenbein, Radek Skoda, Federico Santoni, André Schaller, and Outi Kilpivaara for helpful discussions and critical comments.
Funding
This work was supported by grants from the "Bernische Krebsliga", the "Werner und Hedy Berger-Janser Stiftung", the "Bernische Stiftung für klinische Krebsforschung", the "Stiftung für klinisch-experimentelle Tumorforschung", and a grant from the Inselspital/Bern University Hospital, all to UN.
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