TY - JOUR AU - Khalife, Jihane AU - Ghose, Jayeeta AU - Martella, Marianna AU - Viola, Domenico AU - Rocci, Alberto AU - Troadec, Estelle AU - Terrazas, Cesar AU - Satoskar, Abhay R. AU - Gunes, Emine Gulsen AU - Dona, Ada AU - Sanchez, James F. AU - Bergsagel, P. Leif AU - Chesi, Marta AU - Pozhitkov, Alex AU - Rosen, Steven AU - Marcucci, Guido AU - Keats, Jonathan J. AU - Hofmeister, Craig C. AU - Krishnan, Amrita AU - Caserta, Enrico AU - Pichiorri, Flavia T1 - MiR-16 regulates crosstalk in NF-κB tolerogenic inflammatory signaling between myeloma cells and bone marrow macrophages PY - 2019/11/01/ AB - 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-κB 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. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.129348 VL - 4 IS - 21 UR - https://doi.org/10.1172/jci.insight.129348 PB - The American Society for Clinical Investigation ER -