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.
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wei
authors.forename: S
authors.initials: S
authors.lastname: Dimicoli
authors.forename: C
authors.initials: C
authors.lastname: Bueso-Ramos
authors.forename: R
authors.initials: R
authors.lastname: Chen
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.forename: D
authors.initials: D
authors.lastname: Neuberg
authors.forename: S
authors.initials: S
authors.lastname: Pierce
authors.forename: Y
authors.initials: Y
authors.lastname: Jia
authors.forename: H
authors.initials: H
authors.lastname: Zheng
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: M
authors.initials: M
authors.lastname: Nguyen
authors.forename: S A
authors.initials: SA
authors.lastname: Wang
authors.forename: B
authors.initials: B
authors.lastname: Ebert
authors.forename: R
authors.initials: R
authors.lastname: Bejar
authors.forename: R
authors.initials: R
authors.lastname: Levine
authors.forename: O
authors.initials: O
authors.lastname: Abdel-Wahab
authors.forename: M
authors.initials: M
authors.lastname: Kleppe
authors.forename: I
authors.initials: I
authors.lastname: Ganan-Gomez
authors.forename: H
authors.initials: H
authors.lastname: Kantarjian
authors.forename: G
authors.initials: G
authors.lastname: Garcia-Manero
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D018952:Antigens, CD34 / Q000378:metabolism; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D023061:Gene Order; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000401:mortality; D015398:Signal Transduction; D051194:Toll-Like Receptor 1 / Q000235:genetics / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D051216:Toll-Like Receptor 6 / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000235:genetics* / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D016209:Interleukin-8; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; D051193:Toll-Like Receptors; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human