The expression pattern of certain genes may someday help doctors to diagnose and predict whether or not an individual has an aggressive form of B-cell chronic lymphocytic leukemia (CLL), Jefferson cancer researchers have found.
Scientists, led by Carlo Croce, M.D., director of Jefferson’s Kimmel Cancer Center and professor and chair of microbiology and immunology at Jefferson Medical College of Thomas Jefferson University in Philadelphia, looked at the expression of genes that encoded microRNAs (miRNAs), tiny pieces of genetic material that are thought to be important in the regulation of gene expression and in the development of cancer. MiRNAs can serve as stop signs for gene expression and protein synthesis, and are thought to play important roles in regulating gene expression in development.
Reporting in both the online and the August 10 print version of the Proceedings of the National Academy of Sciences, the researchers – taking advantage of a microarray chip Dr. Croce and his colleagues designed that carries all the known human miRNA genes – compared the expression of miRNA genes in human CLL samples with that of normal white blood cells, or lymphocytes, called CD5+ B cells. CLL, the most common adult leukemia in the Western world, is characterized by an abnormal increase in the number of B cells.
“We found two specific genetic signatures,” Dr. Croce says. One expression pattern of miRNA genes in CLL correlated with a deletion of a chromosomal region called 13q14. This region contained two small miRNA genes that are turned off in about 60 percent of CLL cases. The deletions at 13q14 represent an indicator of a good prognosis for the disease, he notes.
The other miRNA signature was associated with mutations in the Ig or immunoglobulin gene, which also indicates a good prognosis, says Dr. Croce. The researchers also found that the expression of one of the miRNA genes, miR-16, was reduced in both signatures.
“This suggests that CLL involves changes in miRNA, and that you can predict the behavior of CLL depending on the miRNA genetic signature,” says Dr. Croce. “We think we might be able to predict CLL behavior based on the miR-16 signature because that is the only common denominator between the two signatures with good prognosis.”
But before using miRNA expression as any kind of clinical biomarker, says Dr. Croce, the results need to be verified in a clinical trial screening thousands of patients.
Dr. Croce and his colleagues had previously shown that deletions in miRNA genes were involved in B-cell CLL. They also had reported that human miRNA genes are frequently located at sites of the genome that are altered in human cancers.
The work might enable scientists to gain a better understanding of the roles of miRNAs in cancer and provide targets for future drug development.
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Calin GA, Liu CG, Sevignani C, Ferracin M, Felli N, Dumitru CD, Shimizu M, Cimmino A, Zupo S, Dono M, Dell'Aquila ML, Alder H, Rassenti L, Kipps TJ, Bullrich F, Negrini M, Croce CM.
MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias.
Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11755-60. Epub 2004 Jul 29.
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