miR-181a is a novel player in the STAT3-mediated survival network of TCRαβ+ CD8+ T large granular lymphocyte leukemia.

Abstract

T-LGL cells arise as a consequence of chronic antigenic stimulation and inflammation and thrive because of constitutive activation of the STAT3 and ERK pathway. Notably, in 40% of patients, constitutive STAT3 activation is due to STAT3 activating mutations, whereas in 60% this is unknown. As miRNAs are amongst the most potent regulators in health and disease, we hypothesized that aberrant miRNA expression could contribute to dysregulation of these pathways. miRNA sequencing in T-LGL leukemia cases and aged-matched healthy control TEMRA cells revealed overexpression of miR-181a. Furthermore, geneset enrichment analysis (GSEA) of downregulated targets of miR-181a implicated involvement in regulating STAT3 and ERK1/2 pathways. Flow cytometric analyses showed increased SOCS3+ and DUSP6+ T-LGL cells upon miR-181a inhibition. In addition, miR-181a-transfected human CD8+ T cells showed increased basal STAT3 and ERK1/2 phosphorylation. By using TL1, a human T-LGL cell line, we could show that miR-181a is an actor in T-LGL leukemia, driving STAT3 activation by SOCS3 inhibition and ERK1/2 phosphorylation by DUSP6 inhibition and verified this mechanism in an independent cell line. In addition, miR-181a inhibition resulted in a higher sensitivity to FAS-mediated apoptosis. Collectively, our data show that miR-181a could be the missing link to explain why STAT3-unmutated patients show hyperactive STAT3.

• Authors: Jorn L J C Assmann, Leticia G Leon, Christiaan J Stavast, Sanne E van den Bogaerdt, Joyce Schilperoord-Vermeulen, Yorick Sandberg, Mar Bellido, Stefan J Erkeland, David J Feith, Thomas P Loughran Jr, Anton W Langerak
• Journal: Leukemia (Leukemia) Vol. 36 Issue 4 Pg. 983-993 (04 2022) ISSN: 1476-5551 [Electronic] England
• PMID: 34873301 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s).

Chemical References

• MIrn181 microRNA, human
• MicroRNAs
• Receptors, Antigen, T-Cell, alpha-beta
• STAT3 Transcription Factor
• STAT3 protein, human

Topics

• CD8-Positive T-Lymphocytes
• Humans
• Leukemia, Large Granular Lymphocytic (genetics)
• MicroRNAs (genetics)
• Receptors, Antigen, T-Cell, alpha-beta
• STAT3 Transcription Factor (genetics)