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Innate Immunity Dysregulation in Myelodysplastic Syndromes

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Technical Report,30 Sep 2012,29 Sep 2015

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University of Texas MD Anderson Cancer Center Houston United States

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We recently identified the deregulation of an innate immune signaling axis formed by Toll-like receptor and the histone demethylase JMJD3 in the bone marrow hematopoietic stemprogenitor cells HSPCs of MDS. The objective and research scope of proposed study is to perform detailed molecular analysis of this pathway to systematically assess its pathological and therapeutic roles in MDS. We have completed large scale expression profiling of key genes of this pathway in primary patient samples. We have evaluated the ex vivo impact of TLR2 overexpression in normal BM CD34 cells. We have also assessed the therapeutic effects of TLR2- interference via shRNA as well as TLR2 specific humanized antibody via preclinical studies in BM CD34 cells of MDS. Major findings of this project include detailed genetic and expression reports of key components of the TLR2-JMJD3 pathway in MDS and the achievement of critical preclinical evidence supporting the inhibition of TLR2 in MDS. Of importance, this information leads to the development of a novel clinical trial targeting innate immune signals through the application of TLR2 antibody OPN305 in patients with low-risk MDS.

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