Approximately 80,000 to 100,000 people in the United States suffer from myeloproliferative disease, a broad category of ailments characterized by overproduction of different types of blood cells. Often these diseases lead to cancers of blood cells.
Now researchers at MIT, the Whitehead Institute for Biomedical Research and Brigham and Women's Hospital have discovered an unusual mechanism underlying this condition. Their findings, published online in the Proceedings of the National Academy of Sciences the week of Dec. 19, could lay the foundation for future drugs to treat the disorders.
As people age, their genes acquire mutations. In a patient with myeloproliferative disease, a mutation occurs in a protein called a kinase, that is, a protein that adds a small molecule called a phosphate to other proteins, in this case proteins involved in blood-cell growth. But the mutation alone will not produce the disease. The mutant kinase, named JAK2V617F, causes the condition only after binding to another molecule. This indirect mechanism for myeloproliferative disease is unusual because many other kinase mutations lead directly to cell proliferation.
"Surprisingly, this mutant kinase is completely dependent on a cell-surface protein for its transforming potential," says MIT biology professor and Whitehead member Harvey Lodish. His lab made the discovery in collaboration with D. Gary Gilliland of Brigham and Women's. Gilliland is also a Howard Hughes Medical Institute investigator.
Gilliland's lab was one of several to identify the precise genetic mutation responsible for myeloproliferative disease when the researchers discovered that the exact same genetic mutation in a kinase called JAK2 causes a number of distinct disorders that fall under the myeloproliferative disease umbrella. After publishing this finding in Cancer Cell in April, Gilliland turned to Lodish lab researchers, who designed experiments that shed light on the mechanism behind the disease.
The mutant kinase floats around the cell, minding its own business, until it binds to a surface protein called a cytokine receptor, which spans the cell membrane and receives hormone signals from the outside. In a normal cell, the kinase remains inactive until a hormone lands on the receptor and activates it. But the mutated kinase doesn't wait for this external signal. Instead, when two mutated kinases are tethered to adjacent cytokine receptors, they activate each other automatically and trigger a series of events that lead to cell proliferation.
This can cause a number of problems. For example, some patients with myeloproliferative disease develop polycythemia vera, a disorder characterized by high red blood cell counts. Others develop myelofibrosis -- their bone marrow becomes dense as fibroblasts multiply.
The involvement of a cytokine receptor explains, in part, why one mutation can produce distinct disorders. Researchers found three different cytokine receptors that interact with the mutated kinase. Thus the mutant kinase is tied to three unique signaling pathways, each of which is associated with a specific type of blood cell.
"Each disorder might depend on a different receptor and the downstream makeup of the individual cell," says Xiaohui Lu, a postdoctoral associate in the Lodish lab and co-lead author on the paper. This information could help pharmaceutical companies develop drugs to treat the disorders, since they now know which cytokine receptors and blood cell production pathways to target.
This study was supported by the National Institutes of Health, the Leukemia and Lymphoma Society, the Doris Duke Charitable Foundation, the Howard Hughes Medical Institute and Amgen Inc.
A version of this article appeared in MIT Tech Talk on December 21, 2005 (download PDF).
