Alterations of the miR-126-3p/POU2AF1/Spi-B Axis and JCPyV Reactivation in Multiple Sclerosis Patients Receiving Natalizumab

Roberta Mancuso; Simone Agostini; Ambra Hernis; Domenico Caputo; Daniela Galimberti; Elio Scarpini; Mario Clerici

doi:10.3389/fneur.2022.819911

Alterations of the miR-126-3p/POU2AF1/Spi-B Axis and JCPyV Reactivation in Multiple Sclerosis Patients Receiving Natalizumab

Front Neurol. 2022 Mar 11:13:819911. doi: 10.3389/fneur.2022.819911. eCollection 2022.

Authors

Roberta Mancuso¹, Simone Agostini¹, Ambra Hernis¹, Domenico Caputo¹, Daniela Galimberti^{2

3}, Elio Scarpini^{2

3}, Mario Clerici^{1

4}

Affiliations

¹ IRCCS Fondazione Don Carlo Gnocchi, Milan, Italy.
² Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.
³ Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy.
⁴ Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.

Abstract

Natalizumab (NTZ) can reactivate human polyomavirus John Cunningham polyomavirus (JCPyV) latent infection and lead to progressive multifocal leukoencephalopathy (PML). NTZ modulates the expression of microRNA-126-3p (miR-126-3p) and its target genes, Spi-B, POU2AF1, and vascular cell adhesion molecule-1 (VCAM-1); Spi-B protein binds the JCPyV regulatory region, initiating early gene transcription. This paper is aimed to evaluate the miR-126-3p and soluble (s)VCAM-1 concentration, Spi-B/POU2AF1 gene expression, and JCPyV activity in patients with multiple sclerosis (MS) before and during 2-years NTZ. Serum miR-126-3p and sVCAM-1 concentration was measured before NTZ and after 1, 12, and 24 months of treatment in 22 MS subjects, 1 patient who developed PML, and 29 healthy controls (HCs). The Spi-B and POU2AF1 expression in blood was analyzed at baseline and at month 24 in 13 patients with MS; results were clusterized based on JCPyV activity. miR-126-3p was significantly downregulated in MS before and during NTZ but was greatly increased in the PML patient. sVCAM-1 concentration was comparable in MS and HCs, and was reduced by NTZ in MS and PML. Spi-B/POU2AF1 expression was significantly increased in MS at baseline and was upregulated by NTZ, particularly in JCPyV-infected patients in whom JCPyV reactivation was detected. Taken together, the results suggest that the modulation of the miR-126-3p/POU2AF1/Spi-B axis associates with JCPyV activity in NTZ-treated patients with MS.

Keywords: JCPyV; circulating microRNA (miRNA); multiple sclerosis; natalizumab (Tysabri®); progressive multifocal leukoencephalopathy (PML); rehabilitation.