New research suggests childhood leukemias are forged by different evolutionary forces than leukemias in older adults.
Researchers used a computational model to characterize the population dynamics of hematopoietic stem cells (HSCs) that give rise to leukemias.
And they found the evolutionary force known as “drift” contributes to leukemia development in young children but not in older adults.
“Basically, leukemia risk early in life may be more dictated by chance than by the typical ‘survival of the fittest’ that characterizes leukemia formation in older adults,” explained study author James DeGregori, PhD, of the University of Colorado School of Medicine in Aurora.
He and his colleagues recounted this discovery in PNAS.
With previous work, the DeGregori lab showed that the inevitable tissue decline associated with aging benefits HSCs with mutations that allow the cells to better adapt to the new ecosystem.
In contrast, the ecosystem of young tissue favors healthy cells. Optimized by millions of years of co-evolution, most mutations make cells less fit for the ecosystem of young, healthy tissue and lead to purging of mutant cells from the tissue.
With the current study, Dr DeGregori and his colleagues made a surprising discovery. Despite the ability of young tissue to select against cells with cancer-causing mutations, the computational model showed increased proportions of specific, mutation-bearing HSCs in the first few years after birth.
And these mutated cells were not dependent on the effect of the mutation on cell fitness. In other words, the mutation-bearing cells were not more fit than cells without the mutations. Instead of the survival-of-the-fittest form of natural selection that drives the evolution of cancer in older adults, there was another force at work.
In fact, the researchers discovered 2 factors that influence the development of childhood leukemia: the small HSC pool size at birth and the high rate of cell division necessary for body growth early in life.
The high rate of cell division increases the risk of leukemia because mutations largely happen during cell divisions. More cell divisions mean more mutations, and this increases the risk that some of these mutations could contribute to leukemia development.
The small HSC pool size influences leukemia development via the evolutionary force known as drift. Drift is the role of chance—the possibility that, despite being less fit, an animal, organism, or HSC with an oncogenic mutation will survive to shift the genetic makeup of the population.
The influence of drift is greater in small populations and, in this case, small stem cell pools. In the small HSC pools of young children, drift becomes important as a lucky genotype may end up with a larger share of the total HSC pool than warranted by its fitness status.
If this lucky cell clone happens to have a mutation that can start the HSC down the path toward leukemia, this drift-driven expansion should increase the risk of leukemia by increasing the number of HSCs with this mutation.
“Thus, early somatic evolution in HSC pools is significantly impacted by drift, with selection playing a lesser role,” Dr DeGregori and his colleagues wrote.
On the other hand, the impact of drift lessens as the HSC pool grows along with an infant’s body to reach adult size. The larger HSC pool size decreases the role of drift in the success of particular cells in the tissue.
In addition, as the pool size reaches its maximum, the HSC division rate slows to a crawl (as these stem cells enter the maintenance rather than growth phase). With a landscape of healthy, youthful tissues and low rates of mutation due to low cell division rates, the odds of leukemia diminish.
“With a large population of healthy cells optimized to young, healthy tissue, the ability of mutations, including cancerous mutations, to drive uncontrolled cell proliferation is reduced,” Dr DeGregori said.
However, in old age, tissue decline promotes selection for adaptive mutations, leading to the expansion of potentially oncogenic HSC clones that will again increase the risk of leukemia.
Thus, this research shows that, in early life, leukemias are driven by mutation and drift. And in later life, leukemias are driven by mutation and selection.
“We show that leukemias of children and older adults are different diseases, forged by different evolutionary forces and propagated under different circumstances,” Dr DeGregori said.
He and his colleagues believe this understanding raises the possibility of a new approach to cancer treatment. Perhaps researchers could find a way to manipulate the parameters of cell evolution or manipulate the tissue ecosystem to decrease cancer risk.
