Significant association between TNFAIP3 inactivation and biased immunoglobulin heavy chain variable region 4-34 usage in mucosa-associated lymphoid tissue lymphoma

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

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

Abstract

Both antigenic drive and genetic change play critical roles in the development of mucosa-associated lymphoid tissue (MALT) lymphoma, 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) 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 nuclear factor-κB (NF-κB) pathway] in ocular adnexal MALT lymphoma; (2) IGHV1-69 was significantly overrepresented (54%) in MALT lymphoma of the salivary gland, but was not associated with mutation in any of the 17 genes investigated; and (3) MALT lymphoma lacked mutations that are frequently seen in other B-cell lymphomas characterized by constitutive NF-κB activities, including mutations in 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 signalling and driving oncogenesis in lymphoma development.

Original languageEnglish
Pages (from-to)3-8
Number of pages6
JournalJournal of pathology
Volume243
Issue number1
Early online date6 Jul 2017
DOIs
Publication statusPublished - 1 Sept 2017

Keywords

  • IGHV usage
  • MALT lymphoma
  • NF-κB
  • TNFAIP3 mutation

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