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 that TLR1, 2 and 6 to be significantly overexpressed in MDS BM CD34+ cells. Deep-sequencing followed by Sanger-resequencing of TLR1, 2, 4 and 6 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-kB 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 shRNA resulted in increased erythroid colony formation. Finally, RNA expression levels of TLR2 and 6 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.

IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells

“…by guest www.bloodjournal.org From and myeloid-derived suppressor cells are activated in MDS. 10,[54][55][56] The signaling protein, IL-1 receptor-associated kinase (IRAK4), has also been shown to be a therapeutic target in MDS. 57 Our findings further support the role of activated innate immune signaling pathways in MDS/AML and suggest that interaction of IL8-CXCR2 with these other pathways needs to be studied in future For personal use only.…”

A plasma microRNA signature as a biomarker for acquired aplastic anemia

“…In addition, pathway analysis identified innate immune pathways related to Toll-like receptors that might be important both in AA and MDS ( Figure 5). 5,37 MiR-146b-5p decreases TNFa expression in THP-1 monocytes by targeted repression of IRAK1 and TRAF 6,38 and miR-146b-5p is involved in feedback regulation of the innate immune response. 39 Previous studies have also described alterations of miR-146a-5p and/or miR-146b-5p levels to be associated with inflammatory diseases.…”

Hypomethylating Agents in Oncohematology

“…Препаратов, зарегистриро-ванных при неэффективном применении азануклеозидов, не существует. Ряд лекарственных средств изучается в клинических исследованиях: азацитидин и децитабин для приема внутрь, модуляторы сигнального пути трансфор-мирующего фактора роста-β (ACE-536 и ACE-011), ана-логи рецептора тромбопоэтина, ингибиторы протеасомы, антагонисты Toll-подобного сигнального пути [37].…”