CLL is the most common form of leukemia in the United States: about 12,000 new cases are diagnosed each year. Unlike most cancers that occur because cells divide uncontrollably, CLL is caused primarily by defective apoptosis. Cells live an unnaturally long time and fail to die when they should. Patients diagnosed with CLL can live for months or years and can have varying responses to chemotherapy, although researchers do not know why this is the case or how to predict a patient's prognosis.
Increased levels of a protein called Mcl-1 have previously been associated with a lack of response to chemotherapy in CLL patients. To explore the mechanisms that might be responsible for these increased levels, Anurag Saxena, M.D., of the University of Saskatchewan and the Royal University Hospital in Saskatoon, Saskatchewan, Canada, and colleagues sequenced the MCL-1 gene from 58 CLL patients and 18 control subjects. They also measured expression levels of MCL-1 mRNA and Mcl-1 protein.
The researchers found insertions of 6 or 18 nucleotides in the promoter region of the MCL-1 gene in 17 of 58 CLL patients and in none of the controls. The insertions were all found in the same site in the promoter, in a region that contains binding sites for several transcription factors. Transcription factors are proteins that initiate or regulate the transcription of DNA into mRNA. Patients with the insertions were more likely to be nonresponsive to chemotherapy, to have rapid disease progression, and to have a shorter overall survival time. The insertion was also associated with higher MCL-1 mRNA and Mcl-1 protein levels, showing that it may be responsible for increased MCL-1 gene expression.
"In this study, we report a novel, previously unreported, 6- or 18-[nucleotide] insertion in the 5' region of the MCL-1 gene in approximately 30% of unselected patients with CLL. The presence of this insertion was associated with higher mRNA and protein expression, rapid disease progression, and failure to respond to chemotherapy and was a prognostic factor...," the authors write.
In an editorial, Shinichi Kitada, M.D., Ph.D., and John C. Reed, M.D., Ph.D., of The Burnham Institute in La Jolla, Calif., discuss the role of Mcl-1 protein in CLL progression. "The discovery of MCL-1 promoter insertions provides further evidence that this gene plays an important role in the biology of CLL and forecasts a day when improved knowledge of the molecular mechanisms responsible for aberrant control of apoptosis regulation in CLL may provide improved prognostic information that guides individualized therapeutic strategies for optimized medical management," they write.
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