miR-21 antagonism abrogates Th17 tumor promoting functions in multiple myeloma
Marco Rossi, Emanuela Altomare, Cirino Botta, Maria Eugenia Gallo Cantafio, Sarai Sarvide, Daniele Caracciolo, Caterina Riillo, Marco Gaspari, Domenico Taverna, Francesco Conforti, Paola Critelli, Bernardo Bertucci, Michelangelo Iannone, Nicoletta Polerà, Domenica Scumaci, Mariamena Arbitrio, Nicola Amodio, Maria Teresa Di Martino, Bruno Paiva, Pierosandro Tagliaferri, Pierfrancesco Tassone
Multiple myeloma (MM) is tightly dependent on inflammatory bone marrow microenvironment. IL-17 producing CD4+ T cells (Th17) sustain MM cells growth and osteoclasts-dependent bone damage. In turn, Th17 differentiation relies on inflammatory stimuli. Here, we investigated the role of miR-21 in Th17-mediated MM tumor growth and bone disease. We found that early inhibition of miR-21 in naive T cells (miR-21i-T cells) impaired Th17 differentiation in vitro and abrogated Th17-mediated MM cell proliferation and osteoclasts activity.
We validated these findings in NOD/SCID-g-NULL mice, intratibially injected with miR-21i-T cells and MM cells. A Pairwise RNAseq and proteome/phosphoproteome analysis in Th17 cells demonstrated that miR-21 inhibition led to upregulation of STAT-1/-5a-5b, STAT-3 impairment and redirection of Th17 to Th1/Th2 like activated/polarized cells. Our findings disclose the role of miR-21 in pathogenic Th17 activity and open the avenue to the design of miR-21-targeting strategies to counteract microenvironment dependence of MM growth and bone disease.
CITATION Leukemia. 2021 Mar;35(3):823-834. doi: 10.1038/s41375-020-0947-1. Epub 2020 Jul 6.