Lymphoma exosomes reprogram the bone marrow

The link between inflammation and cancer is particularly strong in Waldenström macroglobulinemia (WM), a diffuse large B-cell lymphoma wherein the majority of patients harbor a constitutively active mutation in the innate immune-signaling adaptor myeloid differentiation primary response 88 (MyD88). MyD88Leu265Pro (MyD88L265P) constitutively triggers the myddosome assembly providing a survival signal for cancer cells.

Recearchers at the National Institute of Chemistry, Slovenia 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.

Schematic representation of EV-mediated MyD88 signaling

exosomes

Lymphoma cells release IgMs and cytokines as well as myddosome-containing exosomes and MV. Recipient cells such as macrophages and mast cells uptake EVs and myddosomes are released into the cytosol, where MyD88wt can be recruited. Myddosomes induce inflammation without receptor activation thus changing the tumor microenvironment.

Manček-Keber M, Lainšček D, Benčina M, Chen JG, Romih R, Hunter ZR, Treon SP, Jerala R. (2018) Extracellular vesicle-mediated transfer of constitutively active MyD88L265P engages MyD88wt and activates signaling. Blood 131(15):1720-1729. [article]

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