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[交流] 【转帖】MicroRNA-TP53 Circuit Connected To Chronic Lymphocytic Leukemia

The interplay between a major tumor-suppressing gene, a truncated chromosome and two sets of microRNAs provides a molecular basis for explaining the less aggressive form of chronic lymphocytic leukemia, an international team of researchers reports in the Jan. 4 edition of the Journal of the American Medical Association.

"Our findings could reveal new mechanisms of resistance to chemotherapy among leukemia patients as this feedback mechanism could help us differentiate between patients with poor or good prognosis," said co-senior author George Adrian Calin, M.D., Ph.D., associate professor in The University of Texas MD Anderson Cancer Center Department of Experimental Therapeutics and co-director of the Center for RNA Interference and Noncoding RNAs.

B cell chronic lymphocytic leukemia (CLL) is the most common form of leukemia among adults, with an estimated 14,990 new cases in 2010 in the United States. It's caused by aberrant versions of infection-fighting B cell lymphocytes, a white blood cell.

Deletion of the long arm of chromosome 13, called 13q, has been associated with less aggressive, or indolent, CLL. In a series of experiments, a team led by Calin and colleagues at MD Anderson and The Ohio State University uncovered the details of that relationship.

"This finding represents the most detailed pathogenetic mechanism involving microRNAs for any human disease," Calin said. MicroRNAs, or miRNAs, are short, single-stranded bits of RNA that regulate the messenger RNA expressed by genes to tell a cell's protein-making machinery which protein to make.

Deletion of 13q unleashes two proteins known to stymie programmed cell death, or apoptosis, a frontline defense against formation and growth of malignant cells, the researchers found. However, it also leads to increased expression of the tumor suppressor gene TP53, which indirectly reduced levels of another protein associated with poor survival among CLL patients. The first effect appears to cause CLL, while the combination of effects keeps it indolent, Calin said.

The team worked with three chromosomal deletions common to CLL:

-- Deletion 13q, causes the abolition or reduction of two miRNAs: miR-15a and miR-16-1. It's the most common form of deletion, occurring in about 55 percent of CLL cases.

-- Deletion 11q occurs in about 18 percent of CLL cases and affects two other miRNAs: miR-34b and miR-34c.

-- The short arm of chromosome 17, called 17p, is home to the tumor-suppressing gene tumor protein p53, or TP53. It is deleted in about 7 percent of CLL.

Patients with deletions at 11q and 17p experience the most aggressive form of the disease.

The researchers analyzed blood samples from 208 CLL patients, comparing the relative expression and activity of the miRNAs and TP53 depending on the type or types of deletions the patients had

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