Myelodysplastic syndromes (MDS) originate from a defective hematopoietic stem cell (HSC), and are defined by blood cytopenias due to ineffective hematopoiesis, myeloid dysplasia, and genomic instability. Overexpression of immune-related genes is widely reported in MDS and chronic innate immune pathway activation increases the risk for developing MDS. We find that TNF receptor associated factor 6 (TRAF6), a ubiquitin ligase within the hub of the innate immune pathway, is overexpressed in low-risk MDS patients, and may explain immune pathway activation in the MDS-initiating HSC. According to our preliminary data, TRAF6 overexpression in mice results in MDS and global mRNA splicing alterations by directly ubiquitinating a splicing factor. Therefore, we hypothesize that aberrant expression of TRAF6 results in HSC defects contributing to MDS by directly regulating the spliceosome. Our long-term goal is to understand MDS by investigating molecular alterations associated with MDS pathogenesis. Central to this goal is our interest in the contribution of innate immune pathway to MDS. The objectives of this proposal are to (1) establish the cellular mechanism of TRAF6 overexpression on HSC function, and MDS initiation and maintenance;and (2) determine the mechanism of altered gene splicing by TRAF6 in MDS. Valuable insight will be gained on how TRAF6 overexpression, a gene upregulated in MDS, may contribute to hematopoietic defects resembling MDS.

Public Health Relevance

Myelodysplastic syndromes (MDS) are a collection of acquired or inherited diseases wherein the bone marrow produces too few blood cells, and patients progress to acute leukemia. We have identified that increased innate immune pathway activation is a common feature in MDS cells. Central to this pathway, TRAF6, may play a role in the abnormal production of blood cells. This grant is designed to understand the function of TRAF6 and to determine its role in causing MDS using mouse models.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK102759-01
Application #
8750283
Study Section
Molecular and Cellular Hematology (MCH)
Program Officer
Bishop, Terry Rogers
Project Start
2014-08-15
Project End
2017-05-31
Budget Start
2014-08-15
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$234,000
Indirect Cost
$84,000
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229