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COLUMBUS , Ohio – A new and unusual class of genes plays an important role in the development of chronic lymphocytic leukemia (CLL), according to new research here. At the same time, these genes may provide a new form of therapy for the disease.
CLL strikes some 9,700 Americans annually, making it the most common adult leukemia in the world. The study found that the loss of two genes for producing small molecules known as microRNAs enables damaged cells to survive, rather than normally self-destructing before they become cancerous. “Our findings show that microRNA genes are involved in the development of CLL,” says principal investigator Carlo M. Croce, professor and chair, Department of Molecular Virology, Immunology and Medical Genetics at Ohio State, and director of the Human Cancer Genetics Program at the OSU Comprehensive Cancer Center. “They also strongly suggest that microRNAs might be used therapeutically for CLL and probably other cancers.” The research is published online in the current issue of the Proceedings of the National Academy of Science. The two microRNA genes are known as miR-15 and miR-16. Earlier work led by Croce showed that about 65 percent of CLL patients have cancer cells that show the loss of, or damage to, these genes. This study shows that the two microRNAs interact closely with a protein known as Bcl-2. That protein stops cells from self-destructing through a natural process known as apoptosis. (In 1984, Croce led the research that discovered the Bcl-2 gene.) In CLL cells and cells from other kinds of cancer, the Bcl-2 protein is present in abnormally high levels. This prevents the malignant cells from self-destructing as they should and leads to tumor growth. In about 95 percent of CLL cases, scientists did not know why Bcl-2 was present at high levels. The current paper now answers that. Croce and his colleagues discovered that the miR-15 and miR-16 microRNAs play an important role in controlling Bcl-2 levels, normally keeping them low. When the two microRNA genes are lost – as often happens in CLL – the levels of Bcl-2 rise, the cells do not self-destruct as they should, allowing cancer to occur. Croce and his colleagues explored the relationship between miR-15 and miR-16 in several experiments. For example, the investigators compared cells from 26 CLL patients with cells from four healthy individuals. The normal cells showed high levels of the two microRNAs and low levels of the Bcl-2 protein; the CLL cells showed just the opposite: low levels of the two microRNAs and high levels of the Bcl-2 protein. In another experiment, the researchers used laboratory-grown leukemia cells that had lost the two microRNAs. These cells showed high levels of Bcl-2. Perhaps most importantly, when the researchers then put genes for miR-15 and miR-16 into the cells, the levels of the Bcl-2 dropped and the cells began to self-destruct through apoptosis. “This finding is significant, and it also suggests that miR-15 and miR-16 provide an effective therapy for tumors that overexpress Bcl-2,” Croce says. “It also suggests that the loss of miR-15 and miR-16, and the resulting over-expression of Bcl-2, is the main mechanism of human CLL development in a major fraction of cases.” Funding from National Cancer Institute, the Italian Ministry of Public Health, the Italian Ministry of University Research, the Italian Association of Cancer Research and a Kimmel Scholar award supported this research. (C) 2005 - Ohio State University Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, Wojcik SE, Aqeilan RI, Zupo S, Dono M, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM.
miR-15 and miR-16 induce apoptosis by targeting BCL2.
Proc Natl Acad Sci U S A. 2005 Sep 15
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