The Burrill Report


A Spanish research consortium has identified the first mutation in a protein responsible for protecting telomeres, uncovering one of the most frequently mutated genes in chronic lymphocytic leukemia.

The new and surprising finding, published by The Spanish Consortium for the study of the Chronic Lymphocytic Leukemia Genome in the journal Nature Genetics, reveals that one of the three DNA-binding proteins at the telomere, known as protection of telomere 1 and coded for by the gene POT1, is a common mutation in chronic lymphocytic leukemia.

Given the critical role of the telomeres—the extra bits of DNA at a chromosome’s end—in protecting both the integrity of protein-coding genes at the end of chromosomes as well as the end of the chromosomes themselves, it’s not surprising that DNA mutations in the region are uncommon. One reason mutations are few is the presence of proteins that bind to the telomere and protect it; defects in these protector proteins are also rare.
“Patients with POT1 mutations belong to the group that has the worst prognosis. Therapeutic intervention affecting this pathway could, therefore, help treat a group of patients whose clinical outcome is currently very poor,” says Elías Campo, scientific director of the chronic lymphocytic leukemia genome project at the Hospital Clínic of Barcelona, one of the consortium partners.

The discovery that POT1 is mutated in this cancer, let alone any cancer, breaks new ground. The protein binds directly to the DNA in the telomere, and is part of a larger complex of proteins and factors, known as the shelterin complex, that sits on the DNA in that region to mark telomeres as distinct from sites of DNA damage. Without the shelterin complex, telomeres with their naturally fragmented ends are exposed to the cell’s DNA damage surveillance and repair mechanisms and are erroneously repaired. Until now, there has not been a mutation in any shelterin complex protein implicated in cancer. The mutation in POT1 disrupts binding of the complex to the DNA, causing numerous telomere and chromosome abnormalities in chronic lymphocytic leukemia cells.


To make this discovery, the group analyzed the genomes of 341 chronic lymphocytic leukemia patients and compared gene sequences from healthy cells to tumor cells and found that POT1 was one of the most frequently mutated, with 3.5 percent of the patients carrying this mutation. Within the subgroup of patients with an especially aggressive form of the disease, that figure rises to 9 percent.

The consortium’s work is just beginning, however. “Once the most frequent genetic and epigenetic changes in [chronic lymphocytic leukemia] development have been decoded,” says Carlos López-Otín, leader of the team from the University of Oviedo, “it's necessary to discover the biochemical mechanisms altered by those changes, in order to be able to improve the diagnosis and treatment of this disease."

Chronic lymphocytic leukemia is a disease that is not characterized by highly common mutations. Previous work from the Spanish consortium showed that the most frequently-repeated mutations are present in only 15 percent of patients. The fact that up to 9 percent of patients shared the POT1 mutation identifies POT1 as one of the most important genes for this disease. This has profound consequences since chronic lymphocytic leukemia is the second most common type of leukemia in adults, accounting for 35 percent of all leukemias.

The Spanish consortium is financed by the Ministry of Economy and Competitiveness and is part of the International Cancer Genome Consortium, whose goal is to obtain comprehensive descriptions of genomic, transcriptomic and epigenomic changes in 50 different tumor types and/or subtypes of clinical and societal importance across the globe. With these new results, they are also revealing novel, fundamental mechanisms of carcinogenesis.


March 22, 2013
http://www.burrillreport.com/article-spanish_researchers_identify_key_mutation_in_cll.html