TNFAIP3 inactivation and biased IGHV4-34 usage in MALT lymphoma

Significant association between 

από Sarah Moody, Leire Escudero-Ibarz, Ming Wang, Alexandra Clipson, Eguzkine Ochoa Ruiz, Deborah Dunn-Walters, Xuemin Xue, Naiyan Zeng, Alistair Robson, Shih-Sung Chuang, Sergio Cogliatti, Hongxiang Liu, John Goodlad, Margaret Ashton-Key, Markus Raderer, Yingwen Bi, Ming-Qing Du στο The Journal of Pathology

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ABSTRACT

Both antigenic drive and genetic change play a critical role in the development of mucosa-associated lymphoid tissue (MALT) lymphoma [EdQ please check change], but neither alone is sufficient for malignant transformation, and lymphoma development critically depends on their cooperation. However, which of these different events concur and how they cooperate in MALT lymphomagenesis is totally unknown. To explore this, we investigated somatic mutations of 17 genes and immunoglobulin heavy chain variable region (IGHV) [EdQ please check change]usage in 179 MALT lymphomas from various sites. We showed that: 1) there was a significant association between the biased usage of IGHV4-34 (binds to the carbohydrate I/i antigens) and inactivating mutation of TNFAIP3 (encoding a global negative regulator of the canonical NF-κB pathway) in ocular adnexal MALT lymphoma; 2) IGHV1-69 was significantly overrepresented (54%) in MALT lymphoma of salivary gland, but not associated with mutation in any of the 17 genes investigated; and 3) MALT lymphoma lacked mutations frequently seen in other B-cell lymphomas characterised by constitutive NF-κB activities, including CD79B, CARD11, MYD88, TNFRSF11A and TRAF3. Our findings show for the first time a significant association between biased usage of autoreactive IGHV and somatic mutation of NF-κB regulators in MALT lymphoma, arguing for their cooperation in sustaining chronic B cell receptor (BCR) signalling [EdQ please check change]and driving oncogenesis in lymphoma development.

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