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 the Peter MacCallum Cancer Center (Peter Mac) in Melbourne, Australia. In 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 Center. 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.

Contact: Sue McGreevey
Massachusetts General Hospital