BCL6 Inactivates Tumor Suppressor Gene In Lymphoma
NEW YORK (Reuters Health) - Constitutive expression of the proto-oncogene BCL6 by human B-cell lymphomas stifles the expression of the p53 tumor suppressor gene, protecting B-cells from apoptosis induced by DNA damage, according to a report in the December 2nd issue of Nature.
"BCL6 is the key genetic lesion in the most common form of human lymphoma, diffuse large B-cell lymphoma," co-author Dr. Riccardo Dalla-Favera told Reuters Health. "The question is, what is the function of this gene and what happens when its expression is abnormal?"
BCL6 is a transcription factor that regulates the expression of other genes, but there were questions regarding which genes were controlled BCL6, Dr. Dalla-Favera explained.
Ordinarily, when DNA is damaged, the cell arrests and either undergoes apoptosis or repairs the DNA, he added. This function is not operative in germinal center B cells "because the cells have to break and rearrange their DNA physiologically in order to produce antibodies."
Dr. Dalla-Favera and co-investigator Dr. Ryan T. Phan, both at Columbia University in New York City, looked to see if inhibition of BCL6 expression would alter p53 expression.
They generated B-cell clones with reduced BCL6 expression using short interfering RNA (siRNA) and observed a two- to three-fold increase in p53 mRNA and protein expression, levels comparable to those in normal naïve B cells that lack BCL6.
"These results suggest that an important function of BCL6 is to allow germinal-centre B cells to tolerate the physiological DNA breaks required for immunoglobulin class switch recombination and somatic hypermutation without inducing a p53-dependent apoptotic response," the investigators write.
However, they also imply that deregulated BCL6 expression promotes lymphomagenesis at least in part by functional inactivation of p53.
"This provides rationale [for] a number of drugs that we know shut off BCL6 and activate p53," Dr. Dalla-Favera said.
Source: Nature 2004;432:635-639. [ Google search on this article ]
MeSH Headings: DNA-Binding Proteins : Lymphoma, Undifferentiated : Nuclear Proteins : Phosphoproteins : Proto-Oncogene Proteins : Protein p53 : Lymphoma, B-Cell : Lymphoma, Intermediate-Grade : Lymphoma, Large-Cell, Diffuse
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