Novel mechanism for blood disease
may lead to new drugs
CAMBRIDGE, Mass. (Dec. 20, 2005) — 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. Researchers 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.
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 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 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 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. 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.
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 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.
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