Northwestern Medicine scientists have uncovered key details about a group of rare but serious blood disorders, which may help inform potential treatments, according to a study published in the Journal of Clinical Investigation.
Myeloproliferative neoplasms (MPNs) are rare blood cancers characterized by the abnormal growth of blood cells. They have long been linked to a key signaling pathway called JAK2/STAT, but the specific details of how they develop have remained unclear.
“These diseases are often driven by abnormal activation of a protein called JAK2,” said Peng Ji, MD, PhD, ‘15 GME, the Marie A. Fleming Research Professor of Pathology in the Divisions of Experimental Pathology and Hematopathology, and senior author of the study. “In earlier research, we discovered that another protein, PLEK2, acts downstream of JAK2 and plays a critical role in mediating JAK2’s effects, helping to drive the progression of MPNs.”
In the current study, Ji and his collaborators aimed to better understand the proteins that work alongside PLEK2, also known as the PLEK2 “signalosome.”
By analyzing protein expression in cultured human blood stem cells, the investigators identified a new contributor, PPIL2, that appears to help cancer cells grow by disabling the tumor suppressor protein p53.
Under normal conditions, p53 works as a tumor suppressor protein that prevents excessive cell growth. PPIL2 effectively marks p53 for degradation, weakening its ability to control cell growth and allowing the disease to advance, according to the findings.
Investigators found that blocking PPIL2 using cyclosporin A, an immunosuppressant drug commonly used for organ transplant patients, led to an increase in p53 levels, restoring its ability to regulate cell growth. In experiments using MPN models — including mice with a mutated JAK2 gene and lab-grown human bone marrow — cyclosporin A significantly reduced the abnormal proliferation of blood cells, according to the findings.
“Even better results were seen when cyclosporin A was combined with another type of drug that also boosts p53,” said Ji, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “This shows that targeting PPIL2 might be a powerful new way to treat MPNs using drugs that are already available.”
While more research is needed to fully understand how cyclosporin A works in MPN patients, this study highlights a promising new target for treatment, Ji said.
Now, Ji and his laboratory are planning to work on developing drugs that more specifically block PPIL2, since cyclosporin A affects many proteins and can have unwanted effects.
“Clinical studies will be needed to test whether this approach works in people, possibly starting by looking at how MPN patients respond to cyclosporin A if they’ve already been treated with it,” Ji said.
The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases grants R01-DK124220 and R01-DK138205; and National Heart, Lung, and Blood Institute grants R01-HL148012, R01-HL150729 and R01-HL169507.
