論文

査読有り 国際誌
2020年4月23日

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

Blood
  • 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
  • 全て表示

136
6
開始ページ
684
終了ページ
697
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1182/blood.2019002654

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 diffuse large B-cell lymphoma (ABC-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 the analysis of 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 indicates 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.

リンク情報
DOI
https://doi.org/10.1182/blood.2019002654
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/32325488
ID情報
  • DOI : 10.1182/blood.2019002654
  • PubMed ID : 32325488

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