OncoLog, Volume 53, Number 1, January 2008 Page: 4
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Making Headway Against
Myeloproliferative DisordersFor years, progress against this family of rare
blood disorders was stagnant, but th recent
discovery of a key geneti mutation hasBy Don Norwood
U ntil very recently,
patients with
myeloproliferative
disorders-hemato-
logical diseases in which the
blood-producing cells in
the bone marrow undergo
abnormal development and
malfunction-faced an uphill
battle in their treatment
because of the relative rarity
of these disorders.
As for other rare diseases, pharmaceu-
tical companies have been hesitant to
develop drugs for myeloproliferative
disorders. Thus, even though these disor-
ders cause myriad health problems and
in some cases lead to acute leukemia,
little headway had been made in finding
effective therapies-that is, until a
recent discovery. This discovery of a key
gene mutation has led to the develop-
ment of new drugs that appear to control
myeloproliferative disorders and their
symptoms, giving new hope to patients
who suffer the diseases' debilitating
effects.
The three main myeloproliferative
disorders are polycythenia vera, essen-
tial thrombocythemia, and primary
myelofibrosis. Patients rften experience
such symptoms as headache, fatigue,
shortness of breath, easy bruising or
bleeding, petechiae, unexplained weight
loss, night sweats, and fever. The symp-
toms unique to the different disorders
are no less debilitating. In those with
polycythemia vera, overproduction of
red blood cells can lead to swelling of
the spleen; patients may also havewidespread itching. For patients with
essential thrombocythemia, excess
platelet production can make the blood
"sticky," slowing blood flow. Patients
with primary myelofibrosis develop
scarring or thickening of the fibers in
the bone marrow, leading to decreased
red blood cell production, anemia, and
low numbers of platelets and white
blood cells; the spleen subsequently
enlarges as it takes over the production
of blood cells from the bone marrow.
Low incidence, big breakthrough
Because of the rarity of myeloprolif-
erative disorders, most organizations
that track disease incidence do not track
these disorders. According to 2001-2004
Surveillance, Epidemiology and End
Results data, the combined annual inci-
dence of myeloproliferative disorders in
the United States was 2.1 per 100,000
individuals. In comparison, the mean
annual incidence of prostate, breast,
lung, and colorectal cancers during that
period was 172 per 100,000 men, 130
per 100,000 women, 63 per 100,000
population, and 51 per 100,000 popula-
tion, respectively.
The progression of and prognosis
for myeloproliferative disorders vary
greatly, as some patients must undergo
only close monitoring of their disease,
whereas others have rapid progression
to advanced-stage disease or even to
acute myelogenous leukemia. Further-
more, myeloproliferative disorders can
develop at any age, and researchers
have yet to identify causes for them.
Even with treatment, these disorders
can be fatal.
The discovery that prompted phar-
maceutical and biotechnology compa-
nies to develop more effective therapies
occurred in 2005, when researchers
found a mutation of the JAK2 gene invery large percentages
of patients with the
three main myelopro-
liferative disorders.
While exact causes
of the disorders remain
unknown, the discov-
ery of the mutation
resulted in the devel-
opment of JAK2
inhibitors, and this
has paid significant
dividends for patients.
Initially discovered by a group of
researchers in France, the JAK2 gene is
mutated in more than 90% of patients
with polycythemia vera and about 50%
each of patients with essential thrombo-
cythemia and primary myelofibrosis.
Physiologically, the JAK2 protein, a
tyrosine kinase, plays an important role
in cell growth. In patients with the
mutation in the JAK2 gene, the JAK2
protein is autophosphorylated, meaning
that it is always active, resulting in
the overproduction of blood cells,
said Srdan Verstovsek, M.D., Ph.D.,
associate professor in the Department
of Leukemia at M. D. Anderson. "The
JAK2 protein helps transfer signals
from growth factors that usually circu-
late in the blood and attach to the
growth factor receptors on the cell sur-
faces," Dr. Verstovsek said. The recep-
tors activate JAK2, which then carries
signals through a cascade of proteins
to the cell nuclei. This tells the cells
to grow.
About half of patients with essential
thrombocythemia or primary myelofibro-
sis do not have the JAK2 mutation.
However, researchers have found that
a small percentage of these patients
have other mutations and that the
JAK2 inhibitors may also be beneficial
for them, said Dr. Verstovsek.4
4 OncoLog " January 20084
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University of Texas M.D. Anderson Cancer Center. OncoLog, Volume 53, Number 1, January 2008, periodical, January 2008; Houston, Texas. (https://texashistory.unt.edu/ark:/67531/metapth903751/m1/4/: accessed June 17, 2024), University of North Texas Libraries, The Portal to Texas History, https://texashistory.unt.edu; crediting UNT Libraries Government Documents Department.