VARI Targeting Marrow Disease

August 30, 2007
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GRAND RAPIDS — Scientists at the Van Andel Research Institute have discovered that a gene called Drf1 could be fundamental to the development of a recently recognized form of cancer once known as “pre-leukemia” or “smoldering leukemia.” VARI researchers believe the finding could have significant diagnostic and prognostic value for clinicians and could provide a novel target for therapy for people with myeloproliferative disease and myelodysplasic syndrome, which are diseases of the bone marrow.

MPD and MDS are characterized by abnormal production of red and white blood cells in bone marrow, and both diseases are typically accompanied by chronic anemia, which requires patients to undergo repeated blood transfusions. According to the American Cancer Society, MDS and MPS are diagnosed in 10,000 to 15,000 patients each year.

Senior Scientific Investigator Art Alberts, Ph.D., and VARI researchers in the Laboratory of Cell Structure and Signal Integrations studied the effects of “knocking out” the Drf1 gene using molecular gene targeting to inhibit its expression. Knocking out the gene, they found, leads to the inefficient production of red blood cells and an inability to make white blood cells, similar to the effects of MDS and MPS. The similarity suggests that the Drf1 gene may play a role in both diseases, according to researchers.

“We focused on Drf1 because the human version of the gene is located in a specific genetic region associated with MDS and an increased likelihood of developing leukemias,” Alberts explained. He said the observations he and his team made might offer some insight into how leukemias associated with MPD take root. A research arm of Alberts’ lab is devoted to targeting that particular family of molecules.

“Over the years, we’ve taken a leading role in understanding how the protein that is encoded by the gene is regulated, so we know quite a bit about how we can use molecular tools to try and alter their activities.”

There are several key unanswered questions that need to be addressed, Alberts said, and experiments have just begun in collaboration with physicians at Spectrum Health to try to answer them.

“We’ve established that this gene has a fundamentally important role in bone marrow homeostasis,” Alberts said. “What we need to do now is extrapolate the findings we did in this particular genetic experiment and move to scanning samples from patients to find out if what is true in the genetic model is also true in people.”

Spectrum physicians and VARI researchers are starting to look at patient samples. It’s all being done anonymously; it’s almost a blind study, because researchers don’t have a lot of information on the patients, Alberts noted. The purpose is to study the biology of the disease on a molecular level, on a cellular level and also in the genetic model, he said.

“The idea is that once we get this information from patients, we can, hopefully, put a system in place where we can actually measure the gene in terms of how much of it is there, if it has been mutated, and ask what might that allow us to predict would be an outcome for patients with myelodysplasic syndrome. One aspect of this particular disease is that, as people progress through it, some of them will develop a full-blown leukemia.”    

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