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Bone marrow microenvironment can contribute
to blood cell disorder
Findings may improve treatment of
myeloproliferative syndrome, leukemia
BOSTON - June 14, 2007 - Disorders of blood cells may begin
in the biological environment where the cells develop, not just
with the cells themselves, according to a study from researchers
at the Massachusetts General Hospital (MGH) and Trescowthick Research
Laboratories at the Peter
MacCallum Cancer Centre (Peter Mac) in Melbourne, Australia.
In the June 15 issue of Cell, the investigators describe
finding that genetic alterations in the bone marrow of mice can
cause a type of myeloproliferative syndrome, an overproduction of
certain blood cells that also occurs in human patients.
"Previously all myeloproliferative syndromes have been considered
to be intrinsic to the blood cells themselves," says Louise
Purton, PhD, of the MGH Center for Regenerative Medicine, formerly
of Peter Mac, who led the study. "This discovery may help us
find better therapies for these disorders, which can be quite difficult
to treat, and also for some leukemias."
How the bone marrow microenvironment contributes to the development
and maintenance of blood cells has been the subject of intense research
interest in recent years. In 2003 MGH researchers found that the
bone-forming osteoblasts that line the marrow cavity can regulate
the production of hematopoietic (blood system) stem cells. Although
it is known that certain blood disorders can affect this microenvironment,
the induction of a blood-cell disease by environmental factors alone
has not been reported previously.
Purton's team has been studying how a group of vitamin A receptor
molecules regulate hematopoietic stem cell (HSC) production and
previously showed that the RAR-gamma receptor was critical to HSC
renewal. In that work they observed that mice in which RAR-gamma
had been knocked out had significantly fewer HSCs and increased
numbers of more mature progenitor cells.
In the current study the investigators observed that mice in which
RAR-gamma had been knocked out also had abnormal hematopoiesis of
mature cells, with an overproduction of several types of white blood
cells. In aged knockout mice, the condition was advanced and strongly
resembled human myeloproliferative syndromes. When the RAR-gamma-negative
knockout mice received transplants of bone marrow from normal mice,
the disorder continued despite the presence of donor-derived, RAR-gamma-positive
hematopoietic cells in the marrow, indicating that the lack of RAR-gamma
in the overall microenvironment was behind the disorder.
"There have been reports of patients with myeloproliferative
syndromes receiving stem cell transplants and relapsing with an
overproliferation of donor-based cells, despite no evidence of any
disease in the donors," says Purton. "That indicates that
what we observed in these knockout mice may be happening in these
patients because their disease also is based in the microenvironment.
Understanding how the microenvironment contributes to such diseases
may lead us to better therapies. We also hope to examine whether
the microenvironment may contribute to the transformation of abnormal
noncancerous blood cells into leukemic cells." Purton is an
instructor in Medicine at Harvard Medical School and also is associated
with the Harvard Stem Cell Institute.
Co-first authors of the Cell report are Carl Walkley, PhD,
and Gemma Haines Olsen of the Peter MacCallum Cancer Centre. Additional
co-authors are Sebastian Dworkin, BSc (Hons), Stewart Fabb, PhD,
Jeremy Swann, BSc (Hons), and Grant McArthur, MBBS, PhD of the Peter
Mac; Susan Westmoreland, VMD, and David Scadden, MD, of MGH; and
Pierre Chambon, MD, Institute of Genetics and Molecular and Cellular
Biology, Strasbourg, France. The study was supported by grants from
the Cancer Council of Victoria, the National Health and Medical
Research Council (Australia), and the National Institutes of Health
(U.S.).
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $500 million
and major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, systems biology, transplantation biology and photomedicine.
MGH and Brigham and Women's Hospital are founding members of Partners
HealthCare HealthCare System, a Boston-based integrated health care
delivery system.
Media Contact: Sue
McGreevey, MGH Public Affairs
Robbin Ray, DFCI
Public Affairs
Physician Referral Service: 1-800-388-4644
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