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Extracellular vesicle-mediated transfer of constitutively active MyD88L265P engages MyD88wt and activates signaling

Mateja Manček-Keber, Duško Lainšček, Mojca Benčina, Jiaji G. Chen, Rok Romih, Zachary R. Hunter, Steven P. Treon and Roman Jerala

Key points

  • MyD88L265P is present in the extracellular vesicles (EVs) secreted by WM cancer cells and triggers signaling in the recipient cells

  • MyD88-containing EVs shape proinflammatory microenvironment in the bone marrow

Abstract

The link between inflammation and cancer is particularly strong in Waldenström's macroglobulinaemia (WM), a diffuse large B-cell lymphoma, wherein the majority of patients harbor a constitutively active mutation in the innate immune signaling adaptor MyD88. MyD88L265P constitutively triggers the myddosome assembly providing a survival signal for cancer cells. Here we report detection and a functional role of MyD88 in the extracellular vesicles (EVs) shed from WM cells. MyD88L265P was transferred via EVs into the cytoplasm of the recipient mast cells and macrophages, recruiting the endogenous MyD88 that triggered the activation of proinflammatory signaling in the absence of receptor activation. Additionally, internalization of EVs containing MyD88L265P was observed in mice with an effect on the bone marrow microenvironment. MyD88-loaded EVs were detected in the bone marrow aspirates of WM patients thus establishing the physiological role of EVs for MyD88L265P transmission and shaping of the proinflammatory microenvironment. Results establish the mechanism of transmission of signaling complexes via EVs to propagate inflammation as a new mechanism of intercellular communication.

  • Submitted September 7, 2017.
  • Accepted January 13, 2018.