Protein helps leukemia cells avoid effects of chemotherapy by appearing dormant

Published on April 16, 2013 at 1:36 AM · No Comments

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.

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