Hundreds of random mutations in leukemia related to aging, not cancer
Hundreds of mutations exist in leukemia cells, but nearly all occur randomly as a part of normal aging and are not related to cancer, new research shows. In many cases only two or three additional genetic changes are required to transform a normal blood cell already dotted with mutations into acute myeloid leukemia (AML) – a blood cancer that develops when too many immature blood cells crowd out healthy cells.
Each AML patient’s leukemia cells hold hundreds of mutations. However, each stem cell acquires about 10 mutations per year. By age 50, a person has accumulated nearly 500 mutations in every blood stem cell. “These random, background mutations occur during cell division and are unrelated to cancer. Our DNA can tolerate a huge number of these hits without any negative consequences. But if a cancer-initiating event occurs in one of these stem cells, it captures the genetic history of that cell, including the earlier mutations, and drives leukemia to develop,” says research co-first author Daniel Link.
The genomes of 24 patients with AML were sequenced, and mutations in their leukemia cells were compared to those in the blood stem cells of healthy individuals. Surprisingly, the total number of mutations varied by age, not by whether a patient had leukemia. So a healthy person in his 40s had about the same number of mutations in his blood stem cells as a leukemia patient of the same age had in his cancer cells. The results help explain why leukemia occurs more frequently as people age. “It is the persistent, random accumulation of mutations in blood stem cells that contributes to the risk of the disease,” says co-first author John Welch.
13 novel “driver” mutations that likely help leukemia to develop were identified, along with a number of additional cooperating mutations that work with the driver mutations to give blood stem cells a growth advantage over other cells. In addition to an initiating driver mutation, apparently only one or two cooperating mutations were important for cancer to occur.
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