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

Blood. 2020 Aug 6;136(6):684-697. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Mice
  • Mice, Transgenic
  • Multiprotein Complexes / physiology*
  • Mutation, Missense
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / physiology
  • NF-kappa B / metabolism
  • Neoplasm Transplantation
  • 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


  • Carrier Proteins
  • HOIL-1L protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • MYD88 protein, human
  • Multiprotein Complexes
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • SHARPIN protein, human
  • Sipl1 protein, mouse
  • Transcription Factors
  • Ubiquitins
  • Polyubiquitin
  • RBCK1 protein, human
  • RNF31 protein, human
  • Rnf31 protein, mouse
  • Ubiquitin-Protein Ligases