MiR-16 regulates crosstalk in NF-B tolerogenic inflammatory signaling between myeloma cells and bone marrow macrophages

Jihane Khalife, Jayeeta Ghose, Marianna Martella, Domenico Viola, Alberto Rocci, Estelle Troadec, Cesar Terrazas, Abhay R. Satoskar, Emine Gulsen Gunes, Ada Dona, James F. Sanchez, P. Leif Bergsagel, Marta Chesi, Alex Pozhitkov, Steven Rosen, Guido Marcucci, Jonathan J. Keats, Craig C. Hofmeister, Amrita Krishnan, Enrico CasertaFlavia Pichiorri

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

High levels of circulating miR-16 in the serum of multiple myeloma (MM) patients are independently associated with longer survival. Although the tumor suppressor function of intracellular miR-16 in MM plasma cells (PCs) has been elucidated, its extracellular role in maintaining a nonsupportive cancer microenvironment has not been fully explored. Here, we show that miR-16 is abundantly released by MM cells through extracellular vesicles (EVs) and that differences in its intracellular expression as associated with chromosome 13 deletion (Del13) are correlated to extracellular miR-16 levels. We also demonstrate that EVs isolated from MM patients and from the conditioned media of MM-PCs carrying Del13 more strongly differentiate circulating monocytes to M2-Tumor supportive macrophages (TAMs), compared with MM-PCs without this chromosomal aberration. Mechanistically, our data show that miR-16 directly targets the IKKα/β complex of the NF-B canonical pathway, which is critical not only in supporting MM cell growth, but also in polarizing macrophages toward an M2 phenotype. By using a miR-15a-16-1-KO mouse model, we found that loss of the miR-16 cluster supports polarization to M2 macrophages. Finally, we demonstrate the therapeutic benefit of miR-16 overexpression in potentiating the anti-MM activity by a proteasome inhibitor in the presence of MM-resident bone marrow TAM.

Original languageEnglish (US)
Article numbere129348
JournalJCI Insight
Volume4
Issue number21
DOIs
StatePublished - Oct 8 2019

ASJC Scopus subject areas

  • Medicine(all)

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    Khalife, J., Ghose, J., Martella, M., Viola, D., Rocci, A., Troadec, E., Terrazas, C., Satoskar, A. R., Gunes, E. G., Dona, A., Sanchez, J. F., Leif Bergsagel, P., Chesi, M., Pozhitkov, A., Rosen, S., Marcucci, G., Keats, J. J., Hofmeister, C. C., Krishnan, A., ... Pichiorri, F. (2019). MiR-16 regulates crosstalk in NF-B tolerogenic inflammatory signaling between myeloma cells and bone marrow macrophages. JCI Insight, 4(21), [e129348]. https://doi.org/10.1172/jci.insight.129348