MYD88 L265P elicits mutation-specific ubiquitination to drive NF-κB activation and lymphomagenesis

Blood. 2021 Mar 25;137(12):1615-1627. doi: 10.1182/blood.2020004918.


Myeloid differentiation primary response protein 88 (MYD88) is a critical universal adapter that transduces signaling from Toll-like and interleukin receptors to downstream nuclear factor-κB (NF-κB). MYD88L265P (leucine changed to proline at position 265) is a gain-of-function mutation that occurs frequently in B-cell malignancies such as Waldenstrom macroglobulinemia. In this study, E3 ligase RING finger protein family 138 (RNF138) catalyzed K63-linked nonproteolytic polyubiquitination of MYD88L265P, resulting in enhanced recruitment of interleukin-1 receptor-associated kinases and elevated NF-κB activation. However, RNF138 had little effect on wild-type MYD88 (MYD88WT). With either RNF138 knockdown or mutation on MYD88 ubiquitination sites, MYD88L265P did not constitutively activate NF-κB. A20, a negative regulator of NF-κB signaling, mediated K48-linked polyubiquitination of RNF138 for proteasomal degradation. Depletion of A20 further augmented MYD88L265P-mediated NF-κB activation and lymphoma growth. Furthermore, A20 expression correlated negatively with RNF138 expression and NF-κB activation in lymphomas with MYD88L265P and in those without. Strikingly, RNF138 expression correlated positively with NF-κB activation in lymphomas with MYD88L265P, but not in those without it. Our study revealed a novel mutation-specific biochemical reaction that drives B-cell oncogenesis, providing a therapeutic opportunity for targeting oncogenic MYD88L265P, while sparing MYD88WT, which is critical to innate immunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinogenesis / genetics*
  • Cell Line, Tumor
  • HEK293 Cells
  • Humans
  • Lymphoma / genetics*
  • Mutation
  • Myeloid Differentiation Factor 88 / genetics*
  • Myeloid Differentiation Factor 88 / metabolism
  • NF-kappa B / metabolism*
  • Ubiquitination*


  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • NF-kappa B