Transcription-coupled genetic instability marks acute lymphoblastic leukemia structural variation hotspots.

Some of the most common cancers found in children are called precursor leukemias, which may start to develop before birth. Cancerous cells often contain alterations to the genetic information in their DNA. In precursor leukemias, the most common genetic changes involve deleting, adding or rearranging segments of the DNA sequence. Several researchers have sequenced the entire DNA of childhood leukemia cells, with the result that almost all of the genetic alterations linked to these conditions have been catalogued. These efforts have shown that certain DNA regions are particularly affected by mutations, but no one knows why errors occur so frequently in these regions. Recent evidence also suggests that transcription – the process of producing useful molecules from a stretch of DNA – can play a role in generating genetic alterations. Heinaniemi et al. have now used a technique called global run-on sequencing to measure the extent of transcription in many different types of leukemia cells. This revealed that in the error-prone DNA regions, two processes – called convergent transcription and transcriptional stalling – interfere with transcription. Both processes temporarily leave the normally double-stranded DNA unzipped as two single strands and free of nucleosomes, which makes DNA more vulnerable to breaking. This would explain how pieces of DNA might be lost, added, or moved to cause the genetic errors that lead to leukemia. Further investigation revealed that two protein complexes called RAG and AID, which rearrange segments of DNA in immune cells, are likely to cause the errors in the vulnerable DNA regions. Different amounts of RAG and AID were present in different subtypes of leukemia cells, and these amounts also varied with the risk classification of the disease. Further studies are now needed to investigate the exact roles of these protein complexes. This could eventually help scientists devise strategies to protect the DNA of people with leukemia from these errors, which could reduce the risk of the cancer reoccurring.