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 Iwaï, Akifumi Takaori‐Kondo
Abstract
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.