Unusual RNAs Linked To Chronic Leukemia, May Help Treat It

CLL strikes some 9,700 Americans annually, making it the most common adult leukemia in the world.

Thestudy found that the loss of two genes for producing small moleculesknown as microRNAs enables damaged cells to survive, rather thannormally self-destructing before they become cancerous.

“Ourfindings show that microRNA genes are involved in the development ofCLL,” says principal investigator Carlo M. Croce, professor and chair,Department of Molecular Virology, Immunology and Medical Genetics atOhio State, and director of the Human Cancer Genetics Program at theOSU Comprehensive Cancer Center. “They also strongly suggest thatmicroRNAs might be used therapeutically for CLL and probably othercancers.”

The research is published online in the current issue of the Proceedings of the National Academy of Science.

Thetwo microRNA genes are known as miR-15 and miR-16. Earlier work led byCroce showed that about 65 percent of CLL patients have cancer cellsthat show the loss of, or damage to, these genes.

This studyshows that the two microRNAs interact closely with a protein known asBcl-2. That protein stops cells from self-destructing through a naturalprocess known as apoptosis. (In 1984, Croce led the research thatdiscovered the Bcl-2 gene.)

In CLL cells and cells from otherkinds of cancer, the Bcl-2 protein is present in abnormally highlevels. This prevents the malignant cells from self-destructing as theyshould and leads to tumor growth. In about 95 percent of CLL cases,scientists did not know why Bcl-2 was present at high levels. Thecurrent paper now answers that.

Croce and his colleaguesdiscovered that the miR-15 and miR-16 microRNAs play an important rolein controlling Bcl-2 levels, normally keeping them low. When the twomicroRNA genes are lost – as often happens in CLL – the levels of Bcl-2rise, the cells do not self-destruct as they should, allowing cancer tooccur.

Croce and his colleagues explored the relationship between miR-15 and miR-16 in several experiments.

Forexample, the investigators compared cells from 26 CLL patients withcells from four healthy individuals. The normal cells showed highlevels of the two microRNAs and low levels of the Bcl-2 protein; theCLL cells showed just the opposite: low levels of the two microRNAs andhigh levels of the Bcl-2 protein.

In another experiment, theresearchers used laboratory-grown leukemia cells that had lost the twomicroRNAs. These cells showed high levels of Bcl-2.

Perhaps mostimportantly, when the researchers then put genes for miR-15 and miR-16into the cells, the levels of the Bcl-2 dropped and the cells began toself-destruct through apoptosis.

“This finding is significant,and it also suggests that miR-15 and miR-16 provide an effectivetherapy for tumors that overexpress Bcl-2,” Croce says. “It alsosuggests that the loss of miR-15 and miR-16, and the resultingover-expression of Bcl-2, is the main mechanism of human CLLdevelopment in a major fraction of cases.”

Funding from NationalCancer Institute, the Italian Ministry of Public Health, the ItalianMinistry of University Research, the Italian Association of CancerResearch and a Kimmel Scholar award supported this research.