Abstract
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.
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Acknowledgements
This work has been supported by the Italian Association for Cancer Research (AIRC), PI: PT. “Special Program Molecular Clinical Oncology - 5 per mille” no. 9980, 2010/15 and its Extension Program 2016/17 no. 9980 and “Innovative Immunotherapeutic Treatments of Human Cancer” Multi Unit Regional No. 16695 (co-financed by AIRC and the CARICAL foundation), 2015/18; PI: PT.
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MR designed research, analyzed data, and wrote the paper; EA performed research, analyzed data, and wrote the paper; CB performed research, analyzed data and wrote the paper; MEGC performed research and analyzed data; SS performed research; DC analyzed data; CR analyzed data; MG performed research, contributed analytical tools and analyzed data; DT performed research and analyzed data; FC performed research; PC performed research; BB performed research; MI performed research; NP performed research; DS performed research; MA analyzed data; NA analyzed and critically revised data; MTDM analyzed data; BP contributed analytical tools, analyzed, and critically revised data and paper; PTagliaferri and PTassone critically revised data and wrote the paper.
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Rossi, M., Altomare, E., Botta, C. et al. miR-21 antagonism abrogates Th17 tumor promoting functions in multiple myeloma. Leukemia 35, 823–834 (2021). https://doi.org/10.1038/s41375-020-0947-1
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DOI: https://doi.org/10.1038/s41375-020-0947-1
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