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Eliminating Influence of Hyperactive Genes that Help Regulate Cell Development Shows Potential as Additional Target Therapy for Chronic Myelogenous Leukemia

Researchers at Cincinnati Children's Zero In on Rac1, Rac2 Genes as Molecular Targets

Tuesday, November 27, 2007

CINCINNATI – In a study published in the Nov. 13 issue of Cancer Cell, researchers at Cincinnati Children's Hospital Medical Center reported that they have discovered that targeting and inactivating two genes can inhibit the onset and spread of chronic myelogenous leukemia (CML) in mice.

When these genes, Rac1 and Rac2, become hyperactive, they prompt a protein linked to leukemia to stimulate the onset and spread of CML, a cancer that originates in blood marrow stem cells. But targeted inactivation of those genes, or using a molecule to nullify their hyperactivity, inhibits the onset of leukemia due to the 'Philadelphia chromosome' fusion protein called BCR-ABL, according to David Williams, M.D., director of Experimental Hematology at Cincinnati Children's and the study's senior author.

These findings are significant given the increase in patients with CML in the United States. According to the National Cancer Institute, 4,500 new cases of CML will be diagnosed in the U.S. by the end of 2007, and about 21,000 U.S. residents currently live with the disease – a number that has been increasing largely due to treatment advances, including bone marrow transplant (which is only appropriate for about 25 percent of patients) and tyrosine kinase inhibitors. These inhibitors are designed to block the tyrosine kinase enzyme's ability to stimulate cellular pathways that lead to the growth of cancer cells.

Despite the success of these treatment advances, the BCR-ABL protein remains persistent in its stimulation of CML onset in some patients, says Dr. Williams. "The persistence of the BCR-ABL protein at the molecular level and development of resistance to this therapy suggest that inhibiting this kinase activity alone is not sufficient to eliminate all leukemic cells," he said. "Our data support the hypothesis that BCR-ABL-induced proliferation of leukemic cells is dependent on Rac activation. Thwarting that activation – either by deletion or treatment with a molecule inhibitor – significantly lessens p210-BCR-ABL's proliferation of leukemic cells. This indicates Rac genes may be important molecular targets for pharmacologic intervention in human CML."

In the study, mice transplanted with normal functioning Rac1 and Rac2 genes and expressing the BCR-ABL leukemia protein developed CML-like manifestations (pulmonary hemorrhage, abnormal proliferation of white blood cells, and enlargement of the spleen), and all died within 40 days. In mice transplanted with BCR-ABL where Rac1 and Rac2 hyperactivity was inhibited, 50 percent were still alive 100 days post transplant.

Along with Cincinnati Children's, the study sites included the Hoxworth Blood Center at the University of Center College of Medicine, the University of North Carolina, Ohio State University Comprehensive Cancer Center and the Oregon Health & Science University Cancer Institute.

The study was funded by the National Institutes of Health, the Leukemia and Lymphoma Society, and the U.S. Department of Defense.

Cincinnati Children's Hospital Medical Center, one of the leading pediatric research institutions in the nation, is dedicated to changing the outcome for children throughout the world. Cincinnati Children's ranks second among all pediatric institutions in the United States in grants from the National Institutes of Health. It has an established tradition of research excellence, with discoveries including the Sabin oral polio vaccine, the surfactant preparation that saves the lives of thousands of premature infants each year, and a rotavirus vaccine that saves the lives of hundreds of thousands of infants around the world each year. Current strategic directions include the translation of basic laboratory research into the development of novel therapeutics for the treatment of disease, and furthering the development of personalized and predictive medicine.