Katherine King, PhD | Aplastic Anemia and MDS International Foundation

Katherine King, PhD

Mechanisms of HSC Suppression in Acquired Aplastic Anemia
Original Research Center: 
Baylor College of Medicine
Pubmed Author Name: 
King K

This AAMDSIF research grant will enable us to do basic and essential work on the effects of inflammatory signaling on bone marrow stem cells. We have known for some time that excessive inflammation can suppress bone marrow; now we are taking the next steps to find out how inflammation injures hematopoietic stem cells. We hope that our research will lead to novel ways to interrupt the development of aplastic anemia.  

2015
First Year Report: 

Excessive inflammation is an important trigger for acquired aplastic anemia. Anti-inflammatory medications, such as steroids, can help treat this condition, but these drugs are only effective in some cases, and they result in unwanted side effects including immune suppression. A deeper understanding of how inflammation causes injury to the blood-forming cells of the bone marrow will lead to safer and more effective ways to treat aplastic anemia.

We have shown, using animal models, that inflammatory signals deplete blood stem cells by forcing them to differentiate, effectively using them up prematurely. We identified a factor, Batf2, that is turned on by inflammatory signals and promotes differentiation of blood stem cells. In this project, we have shown that artificially turning on Batf2 in blood stem cells makes them differentiate prematurely. We are now in the process of antagonizing Batf2, and we hope to show that by suppressing Batf2 we can not only stop premature differentiation but also protect blood stem cells from overuse. This research may identify a new method to safeguard the bone marrow function of patients with persistent inflammation.

The proposed research is relevant to human health because it will uncover how blood stem cells respond to inflammation, especially with respect to the inflammatory cytokine interferon gamma. A mechanistic understanding of this process will lead to new therapeutic approaches to protect or enhance blood production during states of inflammation such as chronic infections and autoimmune diseases.

Final Report: 

Excessive inflammation is an important trigger for acquired aplastic anemia. Anti-inflammatory medications, such as steroids, can help treat this condition, but these drugs are only effective in some cases, and they result in unwanted side effects including immune suppression. A deeper understanding of how inflammation causes injury to the blood-forming cells of the bone marrow will lead to safer and more effective ways to treat aplastic anemia.

We used a mouse model to show that inflammatory signals deplete blood stem cells by forcing them to differentiate, effectively using them up prematurely. We identified a factor called Batf2 that is turned on by inflammatory signals and promotes differentiation of blood stem cells. In this project, we showed that artificially turning on Batf2 in blood stem cells makes them differentiate prematurely. Conversely, silencing Batf2 prevents inflammation-induced stem cell differentiation. In other words, by suppressing Batf2 we can not only stop premature differentiation but also protect blood stem cells from overuse. This research may identify a new method to safeguard the bone marrow function of patients with persistent inflammation.

The proposed research is relevant to human health because it will uncover how blood stem cells respond to inflammation, especially with respect to the inflammatory cytokine interferon gamma. A mechanistic understanding of this process will lead to new therapeutic approaches to protect or enhance blood production during states of inflammation such as chronic infections and autoimmune diseases.

The Liviya Anderson Research Grant from the Aplastic Anemia and MDS International Foundation has been a pivotal source of support to my young lab as we sought to produce preliminary data and publications to support more substantial independent funding. With this support, I was able to publish a key paper in Cell Reports that included much of the preliminary data for a new R01 grant from the NIH that was recently funded and will allow us to continue these studies. Having a chance to meet Liviya Anderson’s father was also a huge privilege for my entire lab and provided us a tremendous sense of motivation to push our research forward. We are extremely grateful and eager to continue our efforts to make a difference for Liviya and other patients like her.