Studying MPNs in the Lab and in Space
Why is it that only some people progress from polycythemia vera or essential thrombocythemia to myelofibrosis? And why do only some people with myelofibrosis progress to AML?
When Catriona Jamieson, MD, PhD, and her colleagues at University of California, San Diego, first asked these questions around 2008, they wanted to identify and understand the factors that fuel progression in established MPNs. Their work was funded in part by the MPN Research Foundation.
Today, her work continues to enlighten our knowledge of progression, and its potential interruption, but always with more questions.
One thing her team found is that people who progressed and had high-risk disease, particularly those who progressed to myelofibrosis, had activated a protein coding gene called APOBEC3C.
“We saw mutations induced by this enzymatic mutator,” she explains. “And it was not radiation. It was not a chemical exposure. It was an antiviral gene that got turned on. We didn’t expect that.”
What became clear is that APOBEC3C was massively upregulated as people started to transition from intermediate to high-risk myelofibrosis, and ultimately to AML. Most people, they discovered, have a natural turnoff switch for APOBEC3C, called ADAR1.
“So ADAR is on our radar because that’s kind of the dimmer switch for APOBEC3C,” says Dr. Jamieson. “What we found was if people had very high APOBEC3C expression, they upregulated ADAR1. But unlike a normal stem cell, they couldn’t shut it off.
“The good news is that we found that we can dial down the activity of ADAR1 with JAK2 inhibitors, (i.e., ruxolitinib). And now we’ve found a much more potent inhibitor we’re calling Rebecsinib,” she adds. “What the MPN Research Foundation has helped us do is understand how it’s working . . . and the biomarkers that we’ll need to get into clinical trials.”
Read the full story about this research in our Spring 2022 Update Newsletter, and about the team’s NASA project that is developing a dedicated stem cell research lab within the International Space Station.