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Newly Discovered Genetic Abnormality Shown to Cause Acute Myeloid Leukemia

Findings Could Expand Potential Therapeutic, Diagnostic Options

LA JOLLA, CA, July 30, 2006—Working in collaboration with international researchers, scientists from The Scripps Research Institute have uncovered a new genetic abnormality that results in the rapid development of acute myeloid leukemia (AML) in animal models. These findings could lead to new ways of diagnosing and controlling development of a variety of human diseases, including leukemia and other cancers that result from certain types of genetic defects.

The study is being published July 30 in an advance, online edition of the journal Nature Medicine.

In the study, the researchers report that a previously unknown form of a fusion protein called AML1-ETO9a taken from patient samples “leads to rapid development of leukemia in a mouse blood cell transplantation model.” The newly discovered protein results from a chromosomal translocation—the exchange of material between dissimilar chromosomes often resulting in the fusing of unrelated genes. These new genes express fusion proteins such as AML1-ETO9a that can produce a host of biological mistakes.

The results showed mice receiving AML1-ETO9a-expressing blood cell transplantation showed signs of the leukemia with anemia, high white blood cell count, and abnormal differential counts. Those receiving only the AML1-ETO protein, the most commonly known fusion protein from this particular chromosomal translocation, remained healthy.

“We thought the AML1-ETO9a protein from patients might cause the onset of leukemia,” said Scripps Research Associate Professor Dong-Er Zhang, who led the study. “Indeed, the AML1-ETO9a fusion protein has shown a clear and strong potential to induce the development of leukemia, at least in animal models.  Since chromosomal translocation is one of the most common genetic abnormalities in AML, we hope this discovery will help in the development of future treatments for this devastating disease.”

AML—the most common form of acute leukemia in adults—is a disease of the bone marrow and blood. Normally, hematopoietic stem cells, which are found in adult bone marrow and other places, produce red blood cells, platelets, and white blood cells. In AML, instead of maturing normally, blood cells remain in an abnormal, immature form. As these abnormal cells proliferate, there is less and less room for healthy blood cells, causing patients to experience symptoms such as infection, anemia, and bleeding. According to the American Cancer Society, more than 9,000 deaths from AML will occur in the United States during 2006.

The new study made an additional finding about the fusion protein, AML1-ETO, which alone is not leukomogenic. However, its co-expression with AML1-ETO9a does result in the “substantially earlier onset of AML.” This may indicate that these two proteins may work together to induce cancer development, the researchers said. Notably, the relative amount of both proteins varies among samples from individuals with AML, suggesting that their expression may provide clues to these patients’ prognosis.

Other authors of the study, titled “A previously unknown alternatively spliced isoform of t(8;21) transcript promotes leukemogenesis,” include Ming Yan, Eiki Kanbe, Luke F. Peterson, Anita Boyapati, and Yang Wang of The Scripps Research Institute; Zixing Chen and Yuqin Miao of the Jiangsu Institute of Hematology, Suzhou, Peoples Republic of China; Cheryl L. Willman and Ming Chen of the New Mexico Cancer Research and Treatment Center; and Janet D. Rowley of the University of Chicago.

The study was supported by the National Institutes of Health and the Stein Endowment.

About The Scripps Research Institute

The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Currently operating from temporary facilities in Jupiter, Scripps Florida will move to its permanent campus in 2009.


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