Toll-like receptor alterations in myelodysplastic syndrome Journal Article
| Authors: | Wei, Y.; Dimicoli, S.; Bueso-Ramos, C.; Chen, R.; Yang, H.; Neuberg, D.; Pierce, S.; Jia, Y.; Zheng, H.; Wang, H.; Wang, X.; Nguyen, M.; Wang, S. A.; Ebert, B.; Bejar, R.; Levine, R.; Abdel-Wahab, O.; Kleppe, M.; Ganan-Gomez, I.; Kantarjian, H.; Garcia-Manero, G. |
| Article Title: | Toll-like receptor alterations in myelodysplastic syndrome |
| Abstract: | Recent studies have implicated the innate immunity system in the pathogenesis of myelodysplastic syndromes (MDS). Toll-like receptor (TLR) genes encode key innate immunity signal initiators. We recently identified multiple genes, known to be regulated by TLRs, to be overexpressed in MDS bone marrow (BM) CD34+ cells, and hypothesized that TLR signaling is abnormally activated in MDS. We analyzed a large cohort of MDS cases and identified TLR1, TLR2 and TLR6 to be significantly overexpressed in MDS BM CD34+ cells. Deep sequencing followed by Sanger resequencing of TLR1, TLR2, TLR4 and TLR6 genes uncovered a recurrent genetic variant, TLR2-F217S, in 11% of 149 patients. Functionally, TLR2-F217S results in enhanced activation of downstream signaling including NF-κB activity after TLR2 agonist treatment. In cultured primary BM CD34+ cells of normal donors, TLR2 agonists induced histone demethylase JMJD3 and interleukin-8 gene expression. Inhibition of TLR2 in BM CD34+ cells from patients with lower-risk MDS using short hairpin RNA resulted in increased erythroid colony formation. Finally, RNA expression levels of TLR2 and TLR6, as well as presence of TLR2-F217S, are associated with distinct prognosis and clinical characteristics. These findings indicate that TLR2-centered signaling is deregulated in MDS, and that its targeting may have potential therapeutic benefit in MDS. © 2013 Macmillan Publishers Limited. |
| Keywords: | signal transduction; controlled study; protein expression; human cell; major clinical study; overall survival; mutation; pathophysiology; flow cytometry; bone marrow cells; reverse transcription polymerase chain reaction; gene expression; models, biological; amino acid substitution; interleukin 1beta; interleukin 4; interleukin 8; genetic variability; immunoglobulin enhancer binding protein; cell differentiation; enzyme activity; toll like receptor 4; myelodysplastic syndrome; amino acid sequence; molecular sequence data; il-8; interleukin-8; western blotting; immunoprecipitation; interleukin 6; base sequence; innate immunity; immunity, innate; antigens, cd34; short hairpin rna; toll-like receptor; toll like receptor; toll like receptor 2; myelodysplastic syndromes; erythroid cells; toll-like receptors; histone demethylase; histone methylation; toll like receptor 1; interleukin 1 receptor associated kinase 1; toll like receptor 6; gene order; international prognostic scoring system; gain of function mutation; jmjd3; toll-like receptor 1; toll-like receptor 6; jumonji domain-containing histone demethylases; toll-like receptor 2 |
| Journal Title: | Leukemia |
| Volume: | 27 |
| Issue: | 9 |
| ISSN: | 0887-6924 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2013-09-01 |
| Start Page: | 1832 |
| End Page: | 1840 |
| Language: | English |
| DOI: | 10.1038/leu.2013.180 |
| PROVIDER: | scopus |
| PUBMED: | 23765228 |
| PMCID: | PMC4011663 |
| DOI/URL: | |
| Notes: | --- - Cited By (since 1996):1 - "Export Date: 1 October 2013" - "CODEN: LEUKE" - "Source: Scopus" |
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