Toll-like receptor alterations in myelodysplastic syndrome

• Published in: Leukemia Vol. 27; no. 9; pp. 1832 - 1840
• Main 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2013; Nature Publishing Group
• Subjects: 692/420/2780/262/2106/2108; 692/699/67/1990/1673; Agonists; Amino Acid Sequence; Amino Acid Substitution; Antigens, CD34 - metabolism; Base Sequence; Bone marrow; Bone Marrow Cells - metabolism; Cancer; Cancer Research; CD34 antigen; Cell Differentiation - genetics; Critical Care Medicine; Cytokines; Deregulation; Erythroid Cells - cytology; Erythroid Cells - metabolism; Gene Expression; Gene mutations; Gene Order; Genes; Genetic aspects; Genetic diversity; Genetic variance; Hematology; Histones; Humans; Immune system; Immunity; Immunity, Innate - genetics; Innate immunity; Intensive; Interleukin 8; Interleukin-8 - genetics; Interleukin-8 - metabolism; Internal Medicine; Jumonji Domain-Containing Histone Demethylases - genetics; Jumonji Domain-Containing Histone Demethylases - metabolism; Leukemia; Medicine; Medicine & Public Health; Models, Biological; Molecular Sequence Data; Mutation; Myelodysplastic syndrome; Myelodysplastic syndromes; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - immunology; Myelodysplastic Syndromes - metabolism; Myelodysplastic Syndromes - mortality; NF-κB protein; Oncology; original-article; Pathogenesis; Pathophysiology; Patients; Penicillin; Physiological aspects; Proteins; Receptors; Ribonucleic acid; Risk factors; RNA; Signal Transduction; Signaling; Stem cells; TLR1 protein; TLR2 protein; TLR4 protein; Toll-Like Receptor 1 - genetics; Toll-Like Receptor 1 - metabolism; Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - metabolism; Toll-Like Receptor 6 - genetics; Toll-Like Receptor 6 - metabolism; Toll-like receptors; Toll-Like Receptors - genetics; Toll-Like Receptors - metabolism; United States; United States > US; JMJD3; innate immunity; IL-8; Toll-like receptor; myelodysplastic syndromes
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2013.180

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.