The Mechanisms Behind Leukemia Development

Findings from a study in eLife turned a spotlight on the pathogenesis of DNA damage associated with the development of leukemia.

Several genome-wide studies conducted over the past several years have contributed to the rapid increase in knowledge of the biology of leukemia. Gene deletions in leukemia bloods cells are often associated with specific DNA regions or genes; however, the underlying mechanisms behind this has remained unknown.

Researchers used several deep sequencing methods, including GRO sequencing, to analyze DNA regions actively read by RNA polymerases.

The results of the study showed that for the first time, DNA damage associated with leukemia occurs in regions in which DNA is transcribed actively. Although the explanatory power of the observed mechanism varies in different forms of leukemia, in the most common form of pediatric leukemia the mechanism explained up to 90% of damages that occur in the gene regions.

Additionally, researchers were able to identify a new, high-risk sub-type of leukemia.

“When we studied the characteristics of a signal that describes gene transcription, we discovered that in regions that are susceptible to damage, gene transcription slows down and temporarily exposes the DNA to enzymes that cause DNA damage,” said lead researcher Merja Heinäniemi.

Authors noted that a similar mechanism was previously discovered in lymphomas, but that the findings improved the understanding of the diversity of genetic damage and leukemia, with the mechanisms by which cancer becomes treatment-resistant.

“It’s kind of like a car crash taking place within blood cells: the transcriptional machineries that are going in different directions within gene regions collide, possibly causing irreversible damage,” said researcher Docent Olli Lohi. “Luckily, most of these accidents are just close calls and they only become dangerous in children whose blood cell progenitors have other predisposing gene damages.”