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Myelodysplasias

Toll-like receptor alterations in myelodysplastic syndrome

Leukemia volume 27, pages 1832–1840 (2013)Cite this article

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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.

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Acknowledgements

This work was supported by grant RP100202 from the Cancer Prevention and Research Institute of Texas (CPRIT), the DOD/Congressionally Directed Medical Research Programs, the MD Anderson Cancer Center Leukemia SPORE grant CA100632, the Evans Foundation and the MD Anderson Cancer Center CCSG CA016672. IG-G was funded by the Regional Ministry of Education of Castilla-la Mancha, Spain, supported by the European Social Fund (ESF). We are thankful to Zhihong Fang, Ying Hu, and Michael Fernandez for their technical help.

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Authors and Affiliations

  1. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Y Wei, S Dimicoli, H Yang, S Pierce, Y Jia, H Zheng, I Ganan-Gomez, H Kantarjian & G Garcia-Manero

  2. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    C Bueso-Ramos, M Nguyen & S A Wang

  3. Department of Human Genetics, Baylor College of Medicine, Houston, TX, USA

    R Chen, H Wang & X Wang

  4. Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    D Neuberg

  5. Hematology, Brigham and Women Hospital Boston, Boston, MA, USA

    B Ebert & R Bejar

  6. Department of Leukemia and Human Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    R Levine, O Abdel-Wahab & M Kleppe

  7. Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Alcala, Alcala de Henares, Spain

    I Ganan-Gomez

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  1. Y Wei
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Correspondence to G Garcia-Manero.

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Wei, Y., Dimicoli, S., Bueso-Ramos, C. et al. Toll-like receptor alterations in myelodysplastic syndrome. Leukemia 27, 1832–1840 (2013). https://doi.org/10.1038/leu.2013.180

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