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

Abstract

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.

Cellular and Mathematical Analyses of LUBAC Involvement in T Cell Receptor-Mediated NF-κB Activation Pathway

“…Importantly, the Q622L polymorphism in HOIP, which enhances the LUBAC activity, is associated with activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL) (44), and c-IAP-1/2-mediated K63-ubiquitination is involved in the LUBAC recruitment and the linear ubiquitination of BCL10 in ABC-DLBCL cells (45). Although some controversy exists regarding the necessity of the LUBAC catalytic activity for ABC-DLBCL pathogenesis (30), LUBAC is crucial for B cell lymphomagenesis through protection against DNA damageinduced cell death (46). Therefore, the suppression of LUBAC activity is a suitable therapeutic target for ABC-DLBCL (44,46,47).…”

“…Although some controversy exists regarding the necessity of the LUBAC catalytic activity for ABC-DLBCL pathogenesis (30), LUBAC is crucial for B cell lymphomagenesis through protection against DNA damageinduced cell death (46). Therefore, the suppression of LUBAC activity is a suitable therapeutic target for ABC-DLBCL (44,46,47).…”

Discovery of linear ubiquitination, a crucial regulator for immune signaling and cell death

“…Linear ubiquitination of components of the activated TNF receptor complex decreases the production of death-inducible complex II containing RIPK1, RIPK3, FADD, and caspase-8, thereby suppressing death receptor-induced programmed cell death, including apoptosis and necroptosis. mouse transplantation model [41]. LUBAC is also involved in resistance to a widely used anticancer drug, cis-platinum [42].…”

“…We further dissected the role of LUBAC‐mediated linear ubiquitination in B lymphoma in mice overexpressing HOIP in B cells. Increased LUBAC activity facilitated B lymphomagenesis by preventing cell death induced by DNA damage and by increasing NF‐κB signaling [41]. Furthermore, a natural compound that specifically inhibits LUBAC suppresses tumor growth in a mouse transplantation model [41].…”

“…Increased LUBAC activity facilitated B lymphomagenesis by preventing cell death induced by DNA damage and by increasing NF‐κB signaling [41]. Furthermore, a natural compound that specifically inhibits LUBAC suppresses tumor growth in a mouse transplantation model [41]. LUBAC is also involved in resistance to a widely used anticancer drug, cis‐platinum [42].…”