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LUBAC accelerates B-cell lymphomagenesis by conferring resistance to genotoxic stress on B cells
| Content Provider | Scilit |
|---|---|
| Author | Jo, Tomoyasu Nishikori, Momoko Kogure, Yasunori Arima, Hiroshi Sasaki, Katsuhiro Sasaki, Yoshiteru Nakagawa, Tomoko Iwai, Fumie Momose, Shuji Shiraishi, Aki Kiyonari, Hiroshi Kagaya, Noritaka Onuki, Tetsuo Shin-Ya, Kazuo Yoshida, Minoru Kataoka, Keisuke Ogawa, Seishi Iwai, Kazuhiro Takaori-Kondo, Akifumi |
| Copyright Year | 2020 |
| Description | The linear ubiquitin chain assembly complex (LUBAC) is a key regulator of NF-κB 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-κB 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-κB signaling. These results indicate that HOIP facilitates lymphomagenesis by preventing cell death and augmenting NF-κB 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. |
| Related Links | https://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2019002654/1725066/blood.2019002654.pdf |
| Ending Page | 697 |
| Page Count | 14 |
| Starting Page | 684 |
| DOI | 10.1182/blood.2019002654 |
| Journal | Blood |
| Issue Number | 6 |
| Volume Number | 136 |
| Language | English |
| Publisher | American Society of Hematology |
| Publisher Date | 2020-08-06 |
| Access Restriction | Open |
| Subject Keyword | Research and Experimental Medicine Cell Death Model Lubac Hoip Nf Κb Signaling Journal: Blood (Vol- 91, Issue- 6) |
| Content Type | Text |
| Resource Type | Article |
