Preclinical research has revealed potential therapeutic targets for
myelodysplastic syndromes (MDS).
Investigators
found evidence to suggest that TRAF6, a toll-like receptor effector
with ubiquitin ligase activity, plays a key role in MDS.
So TRAF6 and
proteins regulated by TRAF6 may be therapeutic targets for MDS.
Daniel Starczynowski, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio, and his colleagues reported these findings in Nature Immunology.
The investigators first found that TRAF6 is overexpressed in hematopoietic stem/progenitor cells from MDS patients.
To more closely examine the role of TRAF6 in MDS, the team created mouse models in which the protein was overexpressed.
“We found that TRAF6 overexpression in mouse hematopoietic stem cells results in impaired blood cell formation and bone marrow failure,” Dr Starczynowski said.
Further investigation revealed that hnRNPA1, an RNA-binding protein and auxiliary splicing factor, is a substrate of TRAF6. And TRAF6 ubiquitination of hnRNPA1 regulates alternative splicing of Arhgap1.
This activates the GTP-binding Rho family protein Cdc42 and accounts for the defects observed in hematopoietic stem/progenitor cells that express TRAF6.
All of these proteins could be potential treatment targets for cases of MDS triggered by overexpression of TRAF6, according to Dr Starczynowski, who said future studies will test their therapeutic potential in mouse models of MDS.
“Based on our paper, a number of therapeutic approaches can be tested and directed against TRAF6 and other related proteins responsible for MDS,” he said.
Beyond the potential for new therapeutic approaches in MDS, this research revealed a new and critical immune-related function for TRAF6, according to the investigators.
TRAF6 regulates RNA isoform expression in response to various pathogens. In the context of the current study, TRAF6’s regulation of RNA isoform expression is important to the function of hematopoietic cells and reveals another dimension to how cells respond to infection, Dr Starczynowski said.
