From Medicineworld.org: Novel mechanism for blood disease
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Novel mechanism for blood disease
As people age, their genes acquire mutations. In a patient with myeloproliferative disease, a mutation occurs in a specific kind of 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 makes myeloproliferative disease an unusual disease of overproduction of cells, since a number of 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 Whitehead Member Harvey Lodish, whose lab made the discovery in collaboration with D. Gary Gilliland of Brigham and Women's. Their results will be published online in Proceedings of the National Academy of Sciences during the week of December 19.
"This paper provides new and important insights into how this gene contributes to the development of myeloproliferative disease and it should provide an important foundation for subsequent development of new drugs," says Gilliland, who 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 they discovered that the exact same genetic mutation in a kinase called JAK2 causes many 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 many problems. For example, some patients with myeloproliferative disease develop polycythemia vera, a disorder characterized by high red blood cell counts. Other patients develop essential thrombocytopenia-clotting problems can develop as their platelet levels rise. Still 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 three distinct disorders. Scientists 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 post-doctoral 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.
Written by Alyssa Kneller.
Source: Whitehead Institute for Biomedical Research
Did you know?
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. Scientists at Whitehead Institute for Biomedical Research and Brigham and Women's Hospital have discovered an unusual mechanism underlying this condition, and their findings may lay the foundation for future drug development.
Medicineworld.org: Novel mechanism for blood disease
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