Abstract
Mucosa-associated lymphoid tissue (MALT) lymphomas most frequently involve the gastrointestinal tract and are the most common subset of extranodal non-Hodgkin lymphoma1 (NHL). Here we describe overexpression of BCL10 , a novel apoptotic signalling gene that encodes an amino-terminal caspase recruitment domain (CARD; ref. 2), in MALT lymphomas due to the recurrent t(1;14)(p22;q32) (ref. 3). BCL10 cDNAs from t(1;14)-positive MALT tumours contained a variety of mutations, most resulting in truncations either in or carboxy terminal to the CARD. Wild-type BCL10 activated NF-κB but induced apoptosis of MCF7 and 293 cells. CARD-truncation mutants were unable to induce cell death or activate NF-κB, whereas mutants with C-terminal truncations retained NF-κB activation but did not induce apoptosis. Mutant BCL10 overexpression might have a twofold lymphomagenic effect: loss of BCL10 pro-apoptosis may confer a survival advantage to MALT B-cells, and constitutive NF-κB activation may provide both anti-apoptotic and proliferative signals mediated via its transcriptional targets.
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Acknowledgements
We thank P. Vandiveer, I.S. Herrington and D. Dodson for manuscript preparation; D. Schuster, C. Becher and C. Reinsch for technical assistance; Y. Zhang, I.M. Subero and T. Springer for help with FISH studies; S. Gesk for assistance with analysis of the sequencing data; and J. Cleveland, J. Downing, G. Grosveld, J. Ihle, M. Kastan, A.T. Look and J. van Deursen for their comments regarding the manuscript. This research was supported in part by Cancer Center Support (CORE) Grant CA-27165 from the National Cancer Institute, the American Lebanese Syrian Associated Charities (ALSAC), St. Jude Children's Research Hospital, the Comité du Rhône de la Ligue Contre le Cancer (Lyon France), Deutsche Krebshilfe Grant 10-0992-Schl3, Wilhelm Sander Stiftung Grant 95.003.2 and the Interdisciplinary Center for Clinical Cancer Research, University of Kiel. B.S. holds a Hermann and Lilly Schilling professorship.
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Zhang, Q., Siebert, R., Yan, M. et al. Inactivating mutations and overexpression of BCL10, a caspase recruitment domain-containing gene, in MALT lymphoma with t(1;14)(p22;q32) . Nat Genet 22, 63–68 (1999). https://doi.org/10.1038/8767
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DOI: https://doi.org/10.1038/8767
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