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

• Published in: Blood 2020-08, Vol.136 (6), p.684-697
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - genetics; B-Lymphocytes - enzymology; B-Lymphocytes - pathology; Carrier Proteins - physiology; Cell Transformation, Neoplastic - genetics; DNA Damage; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Intracellular Signaling Peptides and Proteins - physiology; Lymphoma, Large B-Cell, Diffuse - enzymology; Lymphoma, Large B-Cell, Diffuse - etiology; Lymphoma, Large B-Cell, Diffuse - genetics; Medicin och hälsovetenskap; Mice; Mice, Transgenic; Multiprotein Complexes - physiology; Mutation, Missense; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - physiology; Neoplasm Transplantation; NF-kappa B - metabolism; Polymorphism, Single Nucleotide; Polyubiquitin - biosynthesis; Protein Processing, Post-Translational; Transcription Factors - physiology; Transcriptome; Ubiquitin-Protein Ligases - analysis; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - physiology; Ubiquitination; Ubiquitins - physiology
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2019002654

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. •LUBAC accelerates B-cell lymphomagenesis through protection of DNA damage–induced apoptosis, thereby promoting AID-mediated mutations.•Inhibition of LUBAC by small molecules is a promising therapeutic strategy for B-cell lymphomas with NF-κB activation. [Display omitted]