LUBAC accelerates B-cell lymphomagenesis by conferring resistance to genotoxic stress on B cells

Tomoyasu Jo, Momoko Nishikori, Yasunori Kogure, Hiroshi Arima, Katsuhiro Sasaki, Yoshiteru Sasaki, Tomoko Nakagawa, Fumie Iwai, Shuji Momose, Aki Shiraishi, Hiroshi Kiyonari, Noritaka Kagaya, Tetsuo Onuki, Kazuo Shin-Ya, Minoru Yoshida, Keisuke Kataoka, Seishi Ogawa, Kazuhiro Iwai, Akifumi Takaori-Kondo

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

The linear ubiquitin chain assembly complex (LUBAC) is a key regulator of NF-kB signaling. Activating single-nucleotide polymorphisms of HOIP, the catalytic subunit of LUBAC, are enriched in patients with activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL), and expression of HOIP, which parallels LUBAC activity, is elevated in ABC-DLBCL samples. Thus, to clarify the precise roles of LUBAC in lymphomagenesis, we generated a mouse model with augmented expression of HOIP in B cells. Interestingly, augmented HOIP expression facilitated DLBCL-like B-cell lymphomagenesis driven by MYD88-activating mutation. The developed lymphoma cells partly shared somatic gene mutations with human DLBCLs, with increased frequency of a typical AID mutation pattern. In vitro analysis revealed that HOIP overexpression protected B cells from DNA damage-induced cell death through NF-kB activation, and analysis of the human DLBCL database showed that expression of HOIP positively correlated with gene signatures representing regulation of apoptosis signaling, as well as NF-kB signaling. These results indicate that HOIP facilitates lymphomagenesis by preventing cell death and augmenting NF-kB signaling, leading to accumulation of AID-mediated mutations. Furthermore, a natural compound that specifically inhibits LUBAC was shown to suppress the tumor growth in a mouse transplantation model. Collectively, our data indicate that LUBAC is crucially involved in B-cell lymphomagenesis through protection against DNA damage-induced cell death and is a suitable therapeutic target for B-cell lymphomas.

Original languageEnglish
Pages (from-to)684-697
Number of pages14
JournalBlood
Volume136
Issue number6
DOIs
Publication statusPublished - 2020 Aug 6

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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