March 29, 2005
Researchers from Brigham and Women's Hospital and Dana-Farber discover cause of several incurable bone marrow malignancies
New, Internet-based research strategy helped identify gene that causes bone marrow cancers, giving researchers new hope in finding treatment
Gary Gilliland, MD, PhD
Using an Internet strategy to rapidly collect blood and tissue samples from far-flung patients, researchers from Brigham and Women's Hospital (BWH) and the Dana-Farber Cancer Institute (DFCI) have identified the cause of three related cancers of the bone marrow called myeloproliferative diseases (MPD).
These diseases are known as clonal disorders of blood — caused by an acquired, rather than inborn, mutation in blood cells — but the gene that causes the diseases had been unknown despite decades of research. The gene discovery gives researchers new hope of developing precise, molecularly targeted therapies for these deadly cancers, for which there is presently no effective treatment. Details of the research appear in the April 2005 issue of Cancer Cell and on the publication's Web site.
Myeloproliferative disorders are diseases in the bone marrow that produce an excess of certain types of blood cells. Bone marrow is the spongy tissue inside the large bones in the body that makes red blood cells (which carry oxygen to all the tissues in the body), white blood cells (which fight infection) and platelets (which make the blood clot). While uncommon, these cancers affect as many as 100,000 people in the United States. They are thus about five times more prevalent than the form of chronic myeloid leukemia (CML) that is caused by a BCR-ABL mutation that is now treated with Gleevec, a well-known example of the efficacy of molecularly targeted therapy of cancer.
Stephanie Lee, MD, MPH
BWH oncology researchers D. Gary Gilliland, MD, PhD, and Ross L. Levine, MD, in collaboration with DFCI clinical researchers Martha Wadleigh, MD, and Stephanie Lee, MD, MPH, and their colleagues used a novel Internet-based clinical protocol to obtain a large number of cheek tissue and blood DNA samples from patients with these diseases. Lee explained that study information was distributed via the Internet through a support group; after interested patients returned an informed consent statement, they were mailed kits for obtaining blood and cheek-swab samples at their next physician's appointments and then the kits were mailed to labs for analysis.
The scientists then used rapid, large-scale DNA sequencing to look for mutations in genes called tyrosine kinases, which act like "on-off" cell growth switches and have been shown to be stuck on "on" in a number of cancers. The mutation searched turned up a single-point mutation in the tyrosine kinase — JAK2 (JAK2 V617F) — that is present in the diseased blood cells. The mutation was present in three specific myeloproliferative diseases, including polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). Implications of this research are similar to the research that eventually yielded Gleevec for treating BCR-ABL-positive CML.
"This discovery represents a tremendous step toward understanding the molecular pathophysiology of these diseases and developing a treatment for these cancers," said Gilliland. "Also, the research strategy of high-throughput DNA sequencing, based on remarkable recent advances in human genome analysis, could be applied to other cancers to discover other therapeutic targets."
According to Lee, "Using the Internet for sample collection allowed the project to obtain samples from 345 participants in less than a year, and we had only received three samples in the previous year from patients at our own institutions."
BWH is a 735-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare System, an integrated health care delivery network. Internationally recognized as a leading academic health care institution, BWH is committed to excellence in patient care, medical research and the training and education of health care professionals. The hospital's preeminence in all aspects of clinical care is coupled with its strength in medical research. A leading recipient of research grants from the National Institutes of Health, BWH conducts internationally acclaimed clinical, basic and epidemiological studies.
Dana-Farber Cancer Institute is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), a designated comprehensive cancer center by the National Cancer Institute.
