Natalizumab-induced POU2AF1/Spi-B upregulation: A possible route for PML development.
- Meira M Clinical Neuroimmunology (M.M., C.S., F.H., M.R., B.F.D., J.K., T.D., L.K., R.L.P.L.), Departments of Biomedicine and Neurology, University Hospital Basel, Switzerland; and Department of Neurology (A.H.), St. Josef-Hospital, Ruhr-University Bochum, Germany.
- Sievers C Clinical Neuroimmunology (M.M., C.S., F.H., M.R., B.F.D., J.K., T.D., L.K., R.L.P.L.), Departments of Biomedicine and Neurology, University Hospital Basel, Switzerland; and Department of Neurology (A.H.), St. Josef-Hospital, Ruhr-University Bochum, Germany.
- Hoffmann F Clinical Neuroimmunology (M.M., C.S., F.H., M.R., B.F.D., J.K., T.D., L.K., R.L.P.L.), Departments of Biomedicine and Neurology, University Hospital Basel, Switzerland; and Department of Neurology (A.H.), St. Josef-Hospital, Ruhr-University Bochum, Germany.
- Haghikia A Clinical Neuroimmunology (M.M., C.S., F.H., M.R., B.F.D., J.K., T.D., L.K., R.L.P.L.), Departments of Biomedicine and Neurology, University Hospital Basel, Switzerland; and Department of Neurology (A.H.), St. Josef-Hospital, Ruhr-University Bochum, Germany.
- Rasenack M Clinical Neuroimmunology (M.M., C.S., F.H., M.R., B.F.D., J.K., T.D., L.K., R.L.P.L.), Departments of Biomedicine and Neurology, University Hospital Basel, Switzerland; and Department of Neurology (A.H.), St. Josef-Hospital, Ruhr-University Bochum, Germany.
- Décard BF Clinical Neuroimmunology (M.M., C.S., F.H., M.R., B.F.D., J.K., T.D., L.K., R.L.P.L.), Departments of Biomedicine and Neurology, University Hospital Basel, Switzerland; and Department of Neurology (A.H.), St. Josef-Hospital, Ruhr-University Bochum, Germany.
- Kuhle J Clinical Neuroimmunology (M.M., C.S., F.H., M.R., B.F.D., J.K., T.D., L.K., R.L.P.L.), Departments of Biomedicine and Neurology, University Hospital Basel, Switzerland; and Department of Neurology (A.H.), St. Josef-Hospital, Ruhr-University Bochum, Germany.
- Derfuss T Clinical Neuroimmunology (M.M., C.S., F.H., M.R., B.F.D., J.K., T.D., L.K., R.L.P.L.), Departments of Biomedicine and Neurology, University Hospital Basel, Switzerland; and Department of Neurology (A.H.), St. Josef-Hospital, Ruhr-University Bochum, Germany.
- Kappos L Clinical Neuroimmunology (M.M., C.S., F.H., M.R., B.F.D., J.K., T.D., L.K., R.L.P.L.), Departments of Biomedicine and Neurology, University Hospital Basel, Switzerland; and Department of Neurology (A.H.), St. Josef-Hospital, Ruhr-University Bochum, Germany.
- Lindberg RL Clinical Neuroimmunology (M.M., C.S., F.H., M.R., B.F.D., J.K., T.D., L.K., R.L.P.L.), Departments of Biomedicine and Neurology, University Hospital Basel, Switzerland; and Department of Neurology (A.H.), St. Josef-Hospital, Ruhr-University Bochum, Germany.
- 2016-04-19
Published in:
- Neurology(R) neuroimmunology & neuroinflammation. - 2016
English
OBJECTIVES
To assess messenger RNA (mRNA) expression of POU2AF1 and Spi-B and their potential regulatory microRNAs (miRNAs) in natalizumab-treated patients with multiple sclerosis and in therapy-associated progressive multifocal leukoencephalopathy (PML).
METHODS
Expression of POU2AF1/Spi-B was analyzed by using real-time reverse transcription PCR assays on isolated B/CD8(+) T lymphocytes and peripheral blood mononuclear cells (PBMCs) from cohorts of untreated and natalizumab-treated patients with and without PML. Longitudinal expression analysis was performed on CD4(+), CD8(+) T and B cells from 14 patients who interrupted natalizumab therapy for 8 weeks. The miRNA profiling was conducted in PBMCs from 5 untreated and 5 natalizumab-treated patients using low-density arrays followed by validation with single miRNAs assays in untreated and natalizumab-treated patients.
RESULTS
POU2AF1 and Spi-B mRNAs were upregulated in B and CD8(+) T cells from natalizumab-treated patients, which was validated in PBMCs from different cohorts of natalizumab-treated patients with and without PML, with a noteworthy higher expression of Spi-B in patients with PML. In contrast, downregulation of POU2AF1/Spi-B expression was measured in B and CD8(+) T cells after natalizumab discontinuation. Seventeen differentially expressed miRNAs including miR-10b, a regulator of POU2AF1 mRNA, were identified in long-term natalizumab-treated patients compared with untreated ones.
CONCLUSIONS
Upregulation of POU2AF1 and Spi-B, known transactivators of the JC virus, the causative agent for PML, and its association with occurrence of PML in natalizumab-treated patients, corroborates POU2AF1/Spi-B as potential biomarkers for PML risk, which merits further evaluation.
To assess messenger RNA (mRNA) expression of POU2AF1 and Spi-B and their potential regulatory microRNAs (miRNAs) in natalizumab-treated patients with multiple sclerosis and in therapy-associated progressive multifocal leukoencephalopathy (PML).
METHODS
Expression of POU2AF1/Spi-B was analyzed by using real-time reverse transcription PCR assays on isolated B/CD8(+) T lymphocytes and peripheral blood mononuclear cells (PBMCs) from cohorts of untreated and natalizumab-treated patients with and without PML. Longitudinal expression analysis was performed on CD4(+), CD8(+) T and B cells from 14 patients who interrupted natalizumab therapy for 8 weeks. The miRNA profiling was conducted in PBMCs from 5 untreated and 5 natalizumab-treated patients using low-density arrays followed by validation with single miRNAs assays in untreated and natalizumab-treated patients.
RESULTS
POU2AF1 and Spi-B mRNAs were upregulated in B and CD8(+) T cells from natalizumab-treated patients, which was validated in PBMCs from different cohorts of natalizumab-treated patients with and without PML, with a noteworthy higher expression of Spi-B in patients with PML. In contrast, downregulation of POU2AF1/Spi-B expression was measured in B and CD8(+) T cells after natalizumab discontinuation. Seventeen differentially expressed miRNAs including miR-10b, a regulator of POU2AF1 mRNA, were identified in long-term natalizumab-treated patients compared with untreated ones.
CONCLUSIONS
Upregulation of POU2AF1 and Spi-B, known transactivators of the JC virus, the causative agent for PML, and its association with occurrence of PML in natalizumab-treated patients, corroborates POU2AF1/Spi-B as potential biomarkers for PML risk, which merits further evaluation.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1212/NXI.0000000000000223
- PMID 27088119
- Persistent URL
- https://sonar.ch/global/documents/110853
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