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