Accession Number:

ADA612322

Title:

Innate Immunity Dysregulation in Myelodysplastic Syndromes

Descriptive Note:

Annual rept. 30 Sep 2013-29 Sep 2014

Corporate Author:

M D ANDERSON CANCER CENTER HOUSTON TX

Personal Author(s):

Report Date:

2014-10-01

Pagination or Media Count:

51.0

Abstract:

We have proposed that an innate immune signaling axis formed by Toll-like receptor activation and maintained by the histone demethylase JMJD3 is deregulated in the bone marrow hematopoietic stem progenitor cells HSPCs of MDS. In this funding year, we have performed large scale expression and mutational analyses of key genes in this pathway in primary patient samples. We have achieved a systematic gene expression profiling of TLR1, 2, 6, JMJD3, IL8, and MYD88 in MDS. We have analyzed TLR2-F217S as a somatic mutation with biological gain-of-function property that occurs in 10 of 150 patients. Through clinical data analysis, we have defined associations of deregulation of TLR2-JMJD3 innate immunity genes with IPSS and survival of patients. At the biological level, we have characterized the impact of TLR2 signaling in primary HSPCs, which indicate that abnormal activation of TLR2 inhibits erythroid differentiation. Finally, we have demonstrated that interference of TLR2-JMJD3 innate immunity signaling through inhibition of TLR2 and JMJD3 rescues the differentiation of erythroid lineage in patients with lower-risk diseases low-risk and intermediate-1. In summary, we have achieved a better understanding of the TLR2-JMJD3 innate immune pathway and its biology in MDS, including identification of potential biomarkers and novel therapeutic targets in this disease.

Subject Categories:

  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE