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Isolating Human Peripheral Blood Mononuclear Cells and CD4+ T cells from Sézary Syndrome Patients for Transcriptomic Profiling
Published on: October 14, 2021
MicroRNA expression in Sezary syndrome: identification, function, and diagnostic potential
Erica Ballabio1, Tracey Mitchell, Marloes S van Kester
1Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
Abstract:
MicroRNAs are commonly aberrantly expressed in many cancers. Very little is known of their role in T-cell lymphoma, however. We therefore elucidated the complete miRNome of purified T cells from 21 patients diagnosed with Sézary Syndrome (SzS), a rare aggressive primary cutaneous T-cell (CD4(+)) lymphoma. Unsupervised cluster analysis of microarray data revealed that the microRNA expression profile was distinct from CD4(+) T-cell controls and B-cell lymphomas. The majority (104 of 114) of SzS-associated microRNAs (P < .05) were down-regulated and their expression pattern was largely consistent with previously reported genomic copy number abnormalities and were found to be highly enriched (P < .001) for aberrantly expressed target genes. Levels of miR-223 distinguished SzS samples (n = 32) from healthy controls (n = 19) and patients with mycosis fungoides (n = 11) in more than 90% of samples. Furthermore, we demonstrate that the down-regulation of intronically encoded miR-342 plays a role in the pathogenesis of SzS by inhibiting apoptosis, and describe a novel mechanism of regulation for this microRNA via binding of miR-199a* to its host gene. We also provide the first in vivo evidence for down-regulation of the miR-17-92 cluster in malignancy and demonstrate that ectopic miR-17-5p expression increases apoptosis and decreases cell proliferation in SzS cells.
Insights
MicroRNAs are dysregulated in Sézary Syndrome (SzS), an aggressive T-cell lymphoma. This study identified specific microRNA signatures and revealed miR-342
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- MicroRNAs (miRNAs) are crucial regulators of gene expression.
- Aberrant miRNA expression is implicated in various cancers.
- The role of miRNAs in T-cell lymphomas, particularly Sézary Syndrome (SzS), remains largely unexplored.
Purpose of the Study:
- To comprehensively analyze the miRNome of T cells in Sézary Syndrome (SzS).
- To identify specific miRNA expression patterns associated with SzS.
- To investigate the functional role of key miRNAs in SzS pathogenesis.
Main Methods:
- Microarray analysis of microRNA expression in purified T cells from SzS patients and controls.
- Unsupervised cluster analysis to compare miRNA profiles.
- Bioinformatic analysis to identify differentially expressed miRNAs and their target genes.
- Functional studies to assess the role of specific miRNAs in apoptosis and proliferation.
Main Results:
- Distinct miRNA expression profiles were observed in SzS T cells compared to healthy controls and B-cell lymphomas.
- A majority of identified SzS-associated miRNAs were down-regulated, correlating with genomic abnormalities.
- miR-223 effectively distinguished SzS samples from healthy controls and mycosis fungoides.
- Down-regulation of miR-342 was found to inhibit apoptosis in SzS pathogenesis.
- A novel regulatory mechanism involving miR-199a* binding to the miR-342 host gene was identified.
- The miR-17-92 cluster was down-regulated in SzS, and ectopic miR-17-5p expression reduced proliferation and increased apoptosis.
Conclusions:
- The miRNome is significantly altered in Sézary Syndrome, offering potential diagnostic and therapeutic targets.
- Specific miRNAs, including miR-223 and miR-342, play critical roles in SzS development and progression.
- Novel regulatory pathways involving miRNAs and their host genes contribute to SzS pathogenesis.
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