Document Detail


Toll-like receptor alterations in myelodysplastic syndrome.
MedLine Citation:
PMID:  23765228     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Y Wei; S Dimicoli; C Bueso-Ramos; R Chen; H Yang; D Neuberg; S Pierce; Y Jia; H Zheng; H Wang; X Wang; M Nguyen; S A Wang; B Ebert; R Bejar; R Levine; O Abdel-Wahab; M Kleppe; I Ganan-Gomez; H Kantarjian; G Garcia-Manero
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-06-14
Journal Detail:
Title:  Leukemia     Volume:  27     ISSN:  1476-5551     ISO Abbreviation:  Leukemia     Publication Date:  2013 Sep 
Date Detail:
Created Date:  2013-09-04     Completed Date:  2013-10-21     Revised Date:  2014-06-30    
Medline Journal Info:
Nlm Unique ID:  8704895     Medline TA:  Leukemia     Country:  England    
Other Details:
Languages:  eng     Pagination:  1832-40     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Amino Acid Substitution
Antigens, CD34 / metabolism
Base Sequence
Bone Marrow Cells / metabolism
Cell Differentiation / genetics
Erythroid Cells / cytology,  metabolism
Gene Expression
Gene Order
Humans
Immunity, Innate / genetics
Interleukin-8 / genetics,  metabolism
Jumonji Domain-Containing Histone Demethylases / genetics,  metabolism
Models, Biological
Molecular Sequence Data
Mutation
Myelodysplastic Syndromes / genetics*,  immunology,  metabolism,  mortality
Signal Transduction
Toll-Like Receptor 1 / genetics,  metabolism
Toll-Like Receptor 2 / genetics,  metabolism
Toll-Like Receptor 6 / genetics,  metabolism
Toll-Like Receptors / genetics*,  metabolism
Grant Support
ID/Acronym/Agency:
CA016672/CA/NCI NIH HHS; CA100632/CA/NCI NIH HHS; K08 DK091360/DK/NIDDK NIH HHS; P30 CA008748/CA/NCI NIH HHS; P30 CA016672/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, CD34; 0/Interleukin-8; 0/Toll-Like Receptor 1; 0/Toll-Like Receptor 2; 0/Toll-Like Receptor 6; 0/Toll-Like Receptors; EC 1.14.11.-/Jumonji Domain-Containing Histone Demethylases; EC 1.14.11.-/KDM6B protein, human
Comments/Corrections

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