Although similarities exist between childhood and adult leukemias, evidence suggests that the cancers don’t share the same genetic roots.
New research hints that childhood leukemia may be able to hijack only young, developing cells—like those found in fetuses and children—not the mature cells of full-grown adults, according to Dr. Thomas Mercher, a director of hematology-oncology research for the French National Institute of Health and Medical Research and the Gustave Roussy Research Institute in Villejuif, France.
To investigate why certain leukemias may prey on immature cells, Mercher and his colleagues gathered genetic samples from both young patients and adults with a particularly aggressive form of acute myeloid leukemia (AML), called acute megakaryoblastic leukemia (AML-M7), and replicated the disease in mouse models. The team’s study, published Oct. 29 in the journal Cancer Discovery, hints at why the cancer appears early in life, often before the affected child reaches 2 years old.
Many of the children’s cells contained genes that had merged together to form new, hybrid genes. Individually, the genes play important roles in blood cell development, but once stuck together, those genes may direct cells to build unusual proteins and ultimately transform into cancerous cells, the researchers theorized. None of these “fusion genes” appeared in a single adult leukemia cell, which hinted that the team might be onto something.
After the researchers published this initial finding, they and other scientists found ample evidence of fusion genes in AML-M7 leukemia. But no one knew exactly what these hybrid genes did or why they appeared only in children.
So, Mercher and his colleagues continued to investigate, focusing their research on a fusion gene known as ETO2–GLIS2. Welding together two normally separate genes, ETO2 and GLIS2, the mutation appears in about 30% of children with AML-M7 and seems linked to poor responses to cancer treatment and low survival rates, the researchers wrote. To learn how this mutation drives cancer, the team observed how the fusion gene seized control of hematopoietic stem cells, cells that normally give rise to healthy blood cells but can get hijacked by leukemia.
The scientists developed a mouse model in which they could turn the ETO2–GLIS2 mutation “on” or “off” in a given tissue inside the mouse. They ran their experiment in both fetal and adult-age mice to see if the fusion gene would affect cells differently depending on the cells’ stage of development. And it did. Blocking ETO2–GLIS2 activation in the same fetal mice flipped the switch back, curbed the cancer growth and allowed stem cells to turn into normal blood once more.
By comparison, the adult stem cells appeared “much less prone to give rise to leukemia” when ETO2–GLIS2 was activated, Mercher said. In fact, the fusion gene did not appear to be a key driver of leukemia progression in adult mice.
These findings suggest that some forms of leukemia develop specifically in children because the properties of the fetal cells differ from those of adult cells, the authors noted in a statement. Findings that also make it possible to propose new target mechanisms in fetal cells and pediatric leukemia in order to improve treatments for these patients. If future research could pinpoint how child-specific mutations cause leukemia, drugs could be developed to stall or stop the disease.