Exploring the Link between Genetic Mutation and Aggressive Leukemia and Lymphoma

Mwe Mwe Chao, M.D

One of the newer physicians in the U-M Blood and Marrow Transplant Program, Mwe Mwe Chao, M.D., a lecturer in pediatrics, is helping to develop clinical care guidelines for pediatric and adult blood and marrow transplants, based on the latest clinical research data. She also studies the effects of a mutated gene called CALM, which is associated with aggressive leukemias and lymphomas in children and adults. CALM is one of several genes involved in endocytosis — an important process cells use to transport needed proteins, growth factors and other molecules across the outer membrane and into the cell.

Several years ago, an infant patient at the U-M Health System died rapidly from an aggressive form of leukemia. The infant’s leukemia cells harbored a mutation in CALM. “It’s called an inversion or a translocation,” Chao says. “CALM literally flips positions to become fused to another gene called MLL.” Leukemia patients with this translocation do not respond well to treatment and often die from the disease.

Although the exact function of the mutated CALM gene is still unknown, Chao and her colleagues suspect that mutations in CALM could change the normal growth signaling on the surface of blood cells. Cell surface receptors bring in signaling molecules called growth factors, which stimulate blood cells to grow and divide. Cells with mutated forms of the gene are unable to shut down growth factor signaling, and so continue dividing abnormally.

“Our research suggests that impaired endocytosis could be a new and important mechanism that contributes to the development of aggressive leukemias and lymphomas,” Chao says.

Studying an Arthritis Drug’s Potential to Prevent and Treat Transplant Complications

Ken Cooke, M.D., assistant professor in the Department of Pediatrics and Communicable Diseases, has a special research interest in a rare, but often lethal, post-transplant complication called idiopathic pneumonia syndrome or IPS. Studies completed in Cooke’s laboratory found that a signaling protein called tumor necrosis factor alpha (TNFa) plays a major role in lung damage that can occur after an allogeneic bone marrow transplant.

Working with research colleague James L.M. Ferrara, M.D., Cooke showed that a drug called etanercept, or Enbrel, which is used to treat patients with severe arthritis, reduced the severity of lung injury in laboratory mice with IPS. Etanercept reduces the inflammation and pain of arthritis by blocking TNFa, the same protein that triggers idiopathic pneumonia syndrome.

Based on the success of animal studies, Cooke gave the drug to three U-M transplant patients who were developing IPS. The results were dramatic. “After one or two doses of etanercept, we saw dramatic improvement in the lungs,” Cooke says. “The patients no longer needed oxygen and were able to leave the ICU.”

Now physicians in the BMT Program are beginning NIH-funded national clinical trials of etanercept in patients who develop post-transplant idiopathic pneumonia syndrome. Cooke plans to study plasma and lung fluids from patients enrolled in the trial to learn more about how the IPS disease process works in humans.

These laboratory insights have been used to develop novel clinical protocols aimed at reducing TNFa levels with specific inhibitors in order to prevent or treat GVHD and pulmonary toxicity in our BMT patients. Cooke has recently received a Scholar in Clinical Research Award from the Leukemia and Lymphoma Program and a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research which will continue to support his translational research in this area.

Investigating the Role of Dendritic Cells in Mediating the Human Immune Response

Assistant Professor of Internal Medicine Pavan Reddy, M.D., studies the molecular and genetic mechanisms responsible for graft-versus-host disease. He is especially interested in dendritic cells — a special type of immune cell, which many scientists believe to be the primary mediator of the human immune response.

Dendritic cells trigger a powerful immune response against lingering cancer cells, a process called the graft-versus-leukemia effect, which occurs after a successful allogeneic bone marrow transplant.

But dendritic cells also can stimulate the immune system to attack the patient’s own skin, liver and gastrointestinal cells. When this happens, the immune response shifts into overdrive and generates the dangerous post-transplant complication called graft-versus-host disease.

Reddy and his research colleague James L.M. Ferrara, M.D., are studying drugs called HDAC inhibitors, which seem to alter the function of dendritic cells in ways that block the firestorm of pro-inflammatory cytokines and reduce the risk of graft-versus-host disease.

“So far, we’ve found that these drugs keep dendritic cells in a slightly immature stage,” Reddy explains. “In this stage, they can’t activate T cells in ways that turn on the immune response leading to graft-versus-host disease. Keeping dendritic cells in this immature stage for a short time after a transplant may protect patients during the time of highest risk for GVHD, without interfering with the important role dendritic cells play in GVL.”

Improving Prognosis with Stem Cell Transplants for Patients with Myeloma

Choon-Kee Lee, M.D

Choon-Kee Lee, M.D., associate professor of internal medicine, is an expert on myeloma — a type of cancer that develops in bone marrow. Lee joined the U-M Blood and Marrow Transplant Program in 2005. He specializes in treating myeloma patients who have an unusually serious, aggressive form of the disease.

“Myeloma is a disease of the elderly,” Lee says. “The average age at diagnosis is 68, so these patients often have other medical conditions which make their care more difficult. With conventional treatment, the average survival time after diagnosis used to be just three to five years. Now that we have learned how to use stem cell transplants from the patient’s own blood, the chances of surviving more than 10 years after diagnosis are about 30 percent.”

Unfortunately, this type of stem cell transplant doesn’t help patients with the most serious form of the disease. Lee’s research focuses on developing a new treatment protocol using bone marrow transplants from family members or unrelated donors to treat these high-risk patients. Unfortunately, donor transplants bring the risk of graft-versus-host disease — a complication that is especially dangerous for an older patient.

“Our goal is to use healthy donor cells to attack the cancer without triggering serious graft-versus-host disease,” Lee adds. “We hope to combine transplant treatment with new types of medication in ways that will reduce toxicity and increase effectiveness.” Nationwide clinical studies to test the safety and effectiveness of this new treatment regimen for myeloma will begin soon.

—SFP

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More translational research initiatives underway in the U-M Blood and Marrow Transplant Program