BreakThrough Digest Medical News |
| Key bone marrow protein identified as potential new leukemia treatment target Posted: 14 Apr 2013 09:00 PM PDT .A new study on how the progression of acute lymphocytic leukemia (ALL) is influenced by the bone marrow environment has demonstrated for the first time that targeting a specialized protein known as osteopontin (OPN) may be an effective strategy to increase the efficacy of chemotherapy in patients with this type of blood cancer. Study data were published online today in Blood, the Journal of the American Society of Hematology (ASH).
Acute lymphocytic leukemia (ALL) is a cancer of white blood cells, which normally fight infection in the body. ALL develops when abnormal white blood cells grow quickly but do not properly develop, crowding out normal cells and inhibiting healthy function. While patients with ALL typically experience good initial responses to treatment with chemotherapy, many suffer relapses and their disease becomes extremely difficult to treat (refractory) when a small percentage of abnormal cells reemerge after having evaded the effects of the cytotoxic drug. Relapsed disease arises from residual malignant cells below the level of detection at the time the patient has his or her initial response (a condition known as minimal residual disease or MRD). Treatment strategies aimed at combating chemotherapy resistance and reducing MRD may have the potential to increase overall survival. Previous studies have demonstrated that, even when MRD is not completely eradicated, a reduction in MRD burden correlates with significantly higher overall survival. One proposed approach to improving chemotherapy efficacy and reducing MRD includes identifying lingering, dormant leukemic cells and forcing them into active cell division to make them responsive to treatment, since chemotherapy targets cells that are rapidly dividing. “Previous studies have suggested that osteopontin (OPN), a protein present in the bone marrow, may regulate the way tumor cells grow and spread throughout the body; however, its specific role in the progression of leukemia has not been well studied,” said study author Dorothy Sipkins, MD, PhD, of the Section of Hematology/Oncology at the University of Chicago. “Our research aimed to understand the interactions of OPN and leukemic cells in specific areas of the bone marrow, known as niches, which may allow the cells to ‘hide’ in the dormant state and evade the effects of chemotherapy.” To better understand the interactions of the leukemic cells and OPN within these bone marrow niches and whether leukemic cells can hide, remain dormant, and evade chemotherapy, Dr. Sipkins and colleagues conducted a series of analyses and experiments in mouse models. They further evaluated how controlling the expression of OPN would affect the activity of the leukemic cells and how that control may better sensitize the leukemic cells to the effects of chemotherapy. Dr. Sipkins’ team found that inhibiting the interaction of the OPN with leukemic cells in the bone marrow niches led the dormant cells to actively proliferate, which allows the chemotherapy to identify and target them. When OPN was blocked using neutralizing antibodies and then followed by chemotherapy treatment, leukemic cells responded to the chemotherapy and overall MRD was significantly reduced. These data suggest that OPN may serve as an anchor for leukemic cells within areas of the bone marrow that allow the cells to remain dormant, encouraging them to localize to these areas. “After examining the interactions between the leukemic cells, OPN, and the bone marrow microenvironment, we learned that the bone marrow environment can promote leukemia cell dormancy, creating a form of resistance to chemotherapy. This is an important target, because if we can disrupt the interaction between the OPN and the leukemic cells, we may be able to make this disease more responsive to chemotherapy,” said Dr. Sipkins. “We’ve traditionally designed therapies that focus solely on the cancer cells, but future strategies for ALL and other blood cancer treatment may be enhanced by targeting not just the cancer cells but the environment with which the cells interact.” Dr. Sipkins and her team further suggest that in order to develop a leukemia treatment that neutralizes OPN, studies would need to assess the potential toxic side effects on normal stem cells that cohabit the bone marrow microenvironment. Alternatively, a therapy could be developed to reinforce the interaction between OPN and leukemia cells, which would help maintain the dormant state in an effort to prevent or slow disease progression. ### Blood, the most cited peer-reviewed publication in the field of hematology, is available weekly in print and online. Blood is the official journal of the American Society of Hematology (ASH), the world’s largest professional society concerned with the causes and treatment of blood disorders. ASH’s mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting blood, bone marrow, and the immunologic, hemostatic, and vascular systems by promoting research, clinical care, education, training, and advocacy in hematology. blood® is a registered trademark of the American Society of Hematology. Contact: Andrea Slesinski |
| Scientists learn what makes nerve cells so strong Posted: 14 Apr 2013 09:00 PM PDT How do nerve cells — which can each be up to three feet long in humans — keep from rupturing or falling apart? Axons, the long, cable-like projections on neurons, are made stronger by a unique modification of the common molecular building block of the cell skeleton. The finding, which may help guide the search for treatments for neurodegenerative diseases, was reported in the April 10 issue of Neuron by researchers at the University of Illinois at Chicago College of Medicine.
Microtubules are long, hollow cylinders that are a component of the cytoskeleton in all cells of the body. They also support transport of molecules within the cell and facilitate growth. They are made up of polymers of a building-block substance called tubulin. “Except for neurons, cells’ microtubules are in constant dynamic flux — being taking apart and rebuilt,” says Scott Brady, professor and head of anatomy and cell biology at UIC and principal investigator on the study. But only neurons grow so long, he said, and once created they must endure throughout a person’s life, as much as 80 to 100 years. The microtubules of neurons are able to withstand laboratory conditions that cause other cells’ microtubules to break apart. Brady had been able to show some time ago that the neuron’s stability depended on a modification of tubulin. “But when we tried to figure out what the modification was, we didn’t have the tools,” he said. Yuyu Song, a former graduate student in Brady’s lab and the first author of the study, took up the question. “It was like a detective story with many possibilities that had to be ruled out one by one,” she said. Song, who is now a post-doctoral fellow at Howard Hughes Medical Institute at Yale School of Medicine, used a variety of methods to determine the nature of the modification and where it occurs. She found that tubulin is modified by the chemical bonding of polyamines, positively charged molecules, at sites that might otherwise be chinks where tubulin could be broken down, causing the microtubules to fall apart. She was also able to show that the enzyme transglutaminase was responsible for adding the protective polyamines. The blocking of a vulnerable site on tubulin would explain the extraordinary stability of neuron microtubules, said Brady. However, convincing others required the “thorough and elegant work” that Song brought to it, he said. “It’s such a radical finding that we needed to show all the key steps along the way.” The authors also note that increased microtubule stability correlates with decreased neuronal plasticity — and both occur in the process of aging and in some neurodegenerative diseases. Continued research, they say, may help identify novel therapeutic approaches to prevent neurodegeneration or allow regeneration. ### Laura Kirkpatrick of Lexicon Pharmaceuticals, Alexander Schilling and Donald Helseth of UIC, Jeffery W. Keillor of the University of Ottawa, and Gail Johnson of the University of Rochester Medical Center also contributed to the study. The study was supported by grants (NS23868 and NS23320) from the National Institute of Neurological Disorders and Stroke. Contact: Jeanne Galatzer-Levy |
| You are subscribed to email updates from BreakThrough Digest Medical News To stop receiving these emails, you may unsubscribe now. | Email delivery powered by Google |
| Google Inc., 20 West Kinzie, Chicago IL USA 60610 | |
