December 19, 2005
Researchers Closer to Understanding How One Mutation Causes Three Different Blood Disorders
A fresh look at the delicate dance of enzymes within living cells
has provided insights into how one genetic mutation can lead to three
distinct blood disorders.
The discovery “provides new and important insights into how
this gene contributes to the development of myeloproliferative
disease,” said D. Gary Gilliland, a Howard Hughes Medical
Institute researcher at Brigham and Women's Hospital and Harvard
Medical School. “It should provide an important foundation for
subsequent development of new drugs,” he added.
“Although relatively rare individually, together these disorders are about five times more common than chronic myelogenous leukemia.”
D. Gary Gilliland
The new research results, found in collaboration with biologist
Harvey Lodish's team at the Whitehead Institute for Biomedical
Research, were announced December 19, 2005, in an immediate early
online publication in the Proceedings of the National Academy of
Sciences.
What the teams of scientists are trying to decipher is the molecular
explanation for how the protein encoded by this single gene - called
JAK2V617F - can be the culprit in three different leukemia-like
diseases. They want to know how and why the protein produced by this
gene cooperates with other signaling proteins to touch off disease.
The three leukemia-related disorders caused by the mutation are each
characterized by abnormal growth of blood system cells. The first,
polycythemia vera, involves ultra-high red blood cell counts. The
second, essential thrombocythemia, results from excess growth of blood
platelets. And the third, myelofibrosis with myeloid metaplasia, stems
from abnormal growth of fibroblast cells, making the bone marrow
abnormally dense.
Patients who have these disorders are generally older, and there are
about 100,000 in the United States. At present, patients with any of
the three disorders receive empirically derived drug treatments similar
to those that used to be used to treat chronic myelogenous leukemia
(CML).
The three blood disorders can all become dangerous forms of adult
leukemia. “They are technically cancers in their own
right,” Gilliland explained. They tend to be slow-growing, and
they are sometimes detected before severe symptoms arise, as is true
with CML. Although relatively rare individually, together these
disorders are about five times more common than CML, Gilliland
said.
The research teams hope their findings will help them develop
targeted drug therapies for the three disorders, similar to what has
already been achieved for CML with the drug Gleevec.
In earlier work, Gilliland and three other teams of investigators
found that the damaging mutation in the gene for JAK2V617F occurs later
in life - and is acquired rather than inherited. It is not yet known
why this single gene mutation causes different disorders in different
patients, but it does show that those disorders have much in common.
Other, more aggressive leukemias are known to result from different
kinds of genetic damage, such as gene rearrangements caused by
chromosome breakage.
The two research teams at Harvard and the Whitehead Institute
studied the mutation, which occurs in a gene that makes an enzyme
called a kinase. This particular kinase is one link in a chain - a
kinase cascade — that sends a signal from the cell surface to the
nucleus, spurring a reaction such as cell division.
The kinase is normally pressed into action by the arrival of a
molecule that docks with a specific receptor sitting on the cell's
surface. Arrival of the outside signal, like guests ringing a doorbell,
sets off a cascade of events inside the cell. The kinase's job, once
the doorbell is rung, is to add a phosphate group to another protein.
This sends a message that eventually reaches the nucleus and sets off
some action, such as cell division.
The problem is that a strategic mutation can change everything. In
these three blood disorders, for example, the mutant gene makes an
abnormal kinase, like a faulty doorbell that won't shut off, and the
kinase constantly transmits a signal down the chain of command, whether
it's needed or not. The signal thus spurs abnormal activity - and too
much growth causes overgrowth of a particular type of blood cell,
leading to leukemia.
The researchers demonstrated that the faulty kinase can only trigger
this excessive growth in cells that have its corresponding receptor.
Since this receptor is found only in certain types of blood cells,
their work helps explain why a mutation in JAK2V617F can trigger
three distinct blood disorders - but has not been found to be
associated with disorders originating in other types of blood
cells.
Although more research is needed, “these studies advance our
understanding of the basis of myeloproliferative diseases,”
Gilliland said. “Ultimately it's going to lead to curative
strategies - we hope.”
|
Jennifer Michalowski
