Altered microRNA Expression Links IL6 and TNF-Induced Inflammaging with Myeloid Malignancy
This week we profile a recent publication in Blood from Dr. Jennifer Grants
(pictured below) and the laboratory of Dr. Aly Karsan (pictured above) at BC Cancer.
Can you provide a brief overview of your lab’s current research focus?
The Karsan Lab at Canada’s Michael Smith Genome Sciences Centre at BC Cancer, led by Distinguished Scientist Dr. Aly Karsan, focuses on understanding the mechanisms of resistance to therapy in the myeloid cancers. Within this area his lab has a major focus in studying how posttranscriptional events initiate and maintain myeloid malignancies.
What is the significance of the findings in this publication?
While it has long been appreciated that myeloid malignancies are associated with inflammaging—aging-associated inflammation that occurs in the absence of infection or injury—it was not yet clear if inflammaging of hematopoietic stem cells preceded the development of myeloid malignancies.
This study revealed how regulation of a microRNA links aging, inflammation and the development of myeloid malignancies. By comparing the transcriptomes of over 250 AML patients, a key player in inflammaging-associated myeloid malignancies emerged—an anti-inflammatory microRNA called miR-146a.
Loss of miR-146a expression in mice promoted the development of myeloid malignancies, premature aging of hematopoietic stem cells and enhanced inflammatory signalling. Blocking the inflammatory factors IL6 and TNF prevented cancer formation, demonstrating the involvement of inflammaging in myeloid malignancies and suggesting that anti-inflammatory therapy may be effective for the treatment strategy.
These findings provide evidence that inflammation plays a key role in aging-associated myeloid malignancies and shed light on the potential of using a novel treatment strategy—anti-inflammatory therapies—for patients with reduced miR-146a expression.
What are the next steps for this research?
We are very interested in the role played by microRNAs in hematopoietic stem cell aging and inflammation in healthy humans. Even during normal aging, the immune system undergoes shifts in immune cell composition, which make elderly people more susceptible to infections and malignancies. We are currently partnering with the BC Generations Project to collect blood samples from younger and older healthy subjects, so we can identify changes in microRNA expression that are associated with aging and/or inflammation. These microRNAs (or the pathways they target) will be good candidates to potentially reverse or prevent immune system dysfunction in aging.
This work was funded by:
This work was supported by the Canadian Institutes of Health Research, the Terry Fox Research Institute, the Leukemia and Lymphoma Society of Canada and the BC Cancer Foundation.