Scientists identify potential drug target for treatment-resistant anemias

June 9, 2013 by Nicole Giese Rura, Whitehead Institute for Biomedical Research

Researchers at Whitehead Institute have identified a protein that is the target of glucocorticoids, the drugs that are used to increase red blood cell production in patients with certain types of anemia, including those resulting from trauma, sepsis, malaria, kidney dialysis, and chemotherapy. The discovery could spur development of drugs capable of increasing this protein's production without causing the severe side effects associated with glucocorticoids.

"This research is medically important, and we are using it to find a better way to increase the production of for these patients," says Harvey Lodish, who is a Whitehead Institute Founding Member and a professor of biology at MIT. "It is also a new insight into how self-renewal in can be controlled, and a new way to think about how we can use an to maintain stem and ."

Anemia occurs due to a breakdown in erythropoiesis, the multi-step process that creates red . Some common can be treated with a recombinant form of the hormone erythropoietin (EPO), which normally stimulates red blood-cell production at a fairly late stage of erythropoiesis.

However, certain anemias fail to respond to EPO, creating a large unmet medical need. In the case of Diamond Blackfan anemia (DBA), patients lack a sufficient number of EPO-responsive cells. Instead, glucocorticoids such as prednisone or are used to treat DBA and other anemias resistant to EPO by increasing the numbers of the later progenitor cells that respond to EPO. These drugs cause a host of negative side effects, including decreased , immunosuppression, stunted growth, and cataracts, all of which are particularly burdensome for young patients.

Earlier work in the Lodish lab determined that glucocorticoids increase red blood cell production by acting on early progenitors of red blood cells, called burst forming unit-erythroids (BFU-Es). During erythropoiesis, BFU-Es produce later progenitors called colony forming unit-erythroids (CFU-Es), which are then stimulated by EPO to generate the pro-erythroblasts that eventually become red blood cells. By dividing numerous times before maturing, BFU-Es have a limited ability to self-renew. After exposure to glucocorticoids, BFU-Es divide more times than usual, which ultimately increases the total number of red blood cells they produce.

To determine how glucocorticoids prolong BFU-Es' self-renewing phase, Lingbo Zhang, a graduate student in the Lodish lab, studied the drugs' effects in mouse BFU-Es. His work is described online this week on the website of the journal Nature.

Zhang determined that glucocorticoids increase the expression of the protein Zfp36l2, which binds to messenger RNAs (mRNAs) that otherwise would push BFU-Es to differentiate. Under the sway of Zfp36l2, BFU-Es undergo additional rounds of self-renewing cell divisions, forming eventually more EPO- responsive CFU-Es and that can increase red blood cell production by up to 20-fold in vitro.

"It's amazing that the body can trigger this process using one essential gene," says Zhang. "But this is still the very beginning. What glucocorticoids are doing in these cells has been like a black box and now we have one piece of what's happening in that box. And that will help us toward our goal to find a hormone or drug that could be used as a replacement for glucocorticoids."

Explore further: The doping-drug Epo has an impact in the brain

More information: ZFP36L2 is required for self-renewal of early burst-forming unit erythroid progenitors, Nature, online on June 9, 2013. DOI: 10.1038/nature12215

Related Stories

The doping-drug Epo has an impact in the brain

June 11, 2012
Sportsmen and women dope with the blood hormone Epo to enhance their performance. Researchers from the University of Zurich now discovered by animal testing that Epo has a performance-enhancing effect in the brain shortly ...

Duke research team identifies a potent growth factor for blood stem cells

October 23, 2012
Duke Medicine researchers studying the interaction of blood stem cells and the niche where they reside have identified a protein that may be a long-sought growth factor for blood stem cells.

Recommended for you

Secrets of longevity protein revealed in new study

January 17, 2018
Named after the Greek goddess who spun the thread of life, Klotho proteins play an important role in the regulation of longevity and metabolism. In a recent Yale-led study, researchers revealed the three-dimensional structure ...

Weight flux alters molecular profile, study finds

January 17, 2018
The human body undergoes dramatic changes during even short periods of weight gain and loss, according to a study led by researchers at the Stanford University School of Medicine.

The HLF gene protects blood stem cells by maintaining them in a resting state

January 17, 2018
The HLF gene is necessary for maintaining blood stem cells in a resting state, which is crucial for ensuring normal blood production. This has been shown by a new research study from Lund University in Sweden published in ...

Magnetically applied MicroRNAs could one day help relieve constipation

January 17, 2018
Constipation is an underestimated and debilitating medical issue related to the opioid epidemic. As a growing concern, researchers look to new tools to help patients with this side effect of opioid use and aging.

Researchers devise decoy molecule to block pain where it starts

January 16, 2018
For anyone who has accidentally injured themselves, Dr. Zachary Campbell not only sympathizes, he's developing new ways to blunt pain.

Scientists unleash power of genetic data to identify disease risk

January 16, 2018
Massive banks of genetic information are being harnessed to shed new light on modifiable health risks that underlie common diseases.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.