Multiple myeloma (MM) is a malignant plasma cell disease that accounts for approximately 10% of all hematologic cancers, dependent on inflammatory bone marrow microenvironment (BMM). Bone disease (BD) is a hallmark of MM and is characterized by severe skeleton damage, reduced quality of life and overall survival. Interleukin (IL)-17 producing CD4+ T cells (Th17) trigger MM cells growth and osteclast-dependent bone damage. In turn, Th17 generation and function rely on inflammatory stimuli. There is compelling evidence that miR-21 is a central player in Th17 effector functions. Our preliminary data have shown that miR-21 is highly upregulated in MM-Th17 isolated from patients with active BD as compared to MM with no active BD and controls. So, we investigated the role of miR-21, which is an inflammation induced miRNA, in Th17-mediated MM tumor growth and bone disease. Indeed, we have been able to negatively modulate Th17 differentiation by a specific inhibitor of miR-21 (mir21i). The overall effect of mir-21 inhibition is the suppression of OCL resorptive activity, thus attenuating Th17 mediated multiple myeloma bone disease (MMBD). We found that Inhibition of miR-21 in naive T cells (miR-21i-T cells) impaired differentiation towards Th17 in vitro. Analysis of miR-21-related molecular pathways in Th17 cells demonstrated upregulation of STAT-1/-5a-5b, downregulation of STAT-3 and redirection of Th17 to Th1/activated like cells as shown by a pair-to-pair RNAseq and proteome/phosphoproteome analysis. Inhibition of Th17 by miR-21 impaired MM cell proliferation and osteoclast activity in vitro. We recapitulated and validated these findings in NOD/SCID gNULL mice, injected intratibially with miR-21i-T cells and MM cells. Our findings disclose the critical involvement of miR-21 in pathogenic Th17 activity and open the avenue to the design of miR-21-targeting strategies to counteract BMM-dependent MM development and related BD.
Inhibition of miR-21 as an innovative approach, to target Bone Disease, related to Th17 cells in Multiple Myeloma
Arbitrio Mariamena;
2019
Abstract
Multiple myeloma (MM) is a malignant plasma cell disease that accounts for approximately 10% of all hematologic cancers, dependent on inflammatory bone marrow microenvironment (BMM). Bone disease (BD) is a hallmark of MM and is characterized by severe skeleton damage, reduced quality of life and overall survival. Interleukin (IL)-17 producing CD4+ T cells (Th17) trigger MM cells growth and osteclast-dependent bone damage. In turn, Th17 generation and function rely on inflammatory stimuli. There is compelling evidence that miR-21 is a central player in Th17 effector functions. Our preliminary data have shown that miR-21 is highly upregulated in MM-Th17 isolated from patients with active BD as compared to MM with no active BD and controls. So, we investigated the role of miR-21, which is an inflammation induced miRNA, in Th17-mediated MM tumor growth and bone disease. Indeed, we have been able to negatively modulate Th17 differentiation by a specific inhibitor of miR-21 (mir21i). The overall effect of mir-21 inhibition is the suppression of OCL resorptive activity, thus attenuating Th17 mediated multiple myeloma bone disease (MMBD). We found that Inhibition of miR-21 in naive T cells (miR-21i-T cells) impaired differentiation towards Th17 in vitro. Analysis of miR-21-related molecular pathways in Th17 cells demonstrated upregulation of STAT-1/-5a-5b, downregulation of STAT-3 and redirection of Th17 to Th1/activated like cells as shown by a pair-to-pair RNAseq and proteome/phosphoproteome analysis. Inhibition of Th17 by miR-21 impaired MM cell proliferation and osteoclast activity in vitro. We recapitulated and validated these findings in NOD/SCID gNULL mice, injected intratibially with miR-21i-T cells and MM cells. Our findings disclose the critical involvement of miR-21 in pathogenic Th17 activity and open the avenue to the design of miR-21-targeting strategies to counteract BMM-dependent MM development and related BD.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
