Genetic target found for pediatric leukemia

Dec 5 2004

A molecular target newly discovered by scientists at two prestigious research institutes may pave the way for new treatments that could combat an aggressive form of leukemia, according to a study to be presented today during the 46th Annual Meeting of the American Society of Hematology (ASH).

Acute lymphoblastic leukemia, a disease in which the bone marrow produces too many lymphoblasts (immature white blood cells), is diagnosed in about 4,000 Americans, primarily children and adolescents, every year. The cancer can affect the body's T-cells or B-cells. The T-cell type (known as T-ALL) accounts for about 15 percent of all cases and was the primary focus of the study.

"This study is an excellent example of the power of the kinds of basic research presented regularly at ASH to result in improved patient care," said Stanley Schrier, M.D., Active Emeritus Professor of Medicine/Hematology at Stanford University School of Medicine and President of the American Society of Hematology. "Only 20 years ago we thought that there was only one form of childhood acute lymphoblastic leukemia. Then we learned that the leukemic transformation could affect T and B lymphocytes, which have very different functions and are accordingly treated somewhat differently. Now we learn that T-ALL progresses via a unique cell signaling system, which is vulnerable to attack."

Researchers at Brigham and Women's Hospital and the Dana-Farber Cancer Institute noted that inhibitors of a membrane receptor called NOTCH1 caused T-ALL cell lines to stop growing, indicating that these cell lines have a requirement for pro-growth signals produced by NOTCH1. Further investigation demonstrated that the sensitive cell lines frequently have mutations in NOTCH1 that lead to abnormal increases in NOTCH1 receptor activity.

Similar or identical NOTCH1 mutations were found in more than half of the samples (55 percent) prepared from the bone marrow lymphoblasts of 96 patients with T-ALL, confirming the observations made in cell lines and suggesting that mutations in NOTCH1 are likely to be the most common underlying cause of this particular human cancer. Mutations in NOTCH1 were no longer seen in samples obtained from patients in remission, indicating that they are acquired during life, not inherited, and were not observed in the lymphoblasts of patients with the other major form of this cancer, B-ALL.

Further studies showed that the increased activity caused by mutated NOTCH1 receptors could be completely inhibited by a drug that turns off an enzyme, gamma-secretase, that is required for NOTCH1 activity. Because inhibitors of gamma-secretase have been under development by the pharmaceutical industry for several years (as possible agents for treatment of Alzeheimer's disease), it should be possible to begin clinical trials of these compounds in patients with refractory T-ALL by early next year.

According to Jon Aster, M.D., Ph.D., Associate Pathologist at Brigham and Women's Hospital and senior author of the study, "Our research provides new insights into the pathogenesis of T-ALL and, most importantly, provides an exciting opportunity for rational targeted therapy in this aggressive form of cancer."

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