It is hoped the new findings by the team from the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project (PCGP) and the Children’s Oncology Group (COG), USA, will lead to new diagnostic tests for patients.
The team, which included a researcher from Radboud University Medical Centre, the Netherlands, studied 1,913 patients, all of whom had B-ALL, to understand the subtype’s genetic basis. Microarray and transcriptome sequencing identified 7.6% of the B-ALL patients had the distinctive genetic profile the scientists wanted to investigate further.
The findings were published last night in Nature Genetics.
Corresponding author Dr Charles Mullighan, of the St Jude Department of Pathology, said: “We discovered a distinct gene pattern in blood samples from some patients in our study and wanted to determine the underlying molecular events behind this signal.”
“Our work revealed that in this type of B-ALL there is a sequence of molecular events that involves the interplay of two transcription factors.”
Transcription factors, which are proteins that bind to specific DNA sequences, regulate the expression of genetic information from DNA to messenger RNA.
ChIP sequencing, which enables researchers to analyse how proteins interact with DNA, revealed the link between the two transcription factors, identifying the rearrangement of the transcription factor gene DUX4 in all cases in this subtype of ALL. This resulted in high-level expression of DUX4.
DUX4 bound to the gene for the transcription factor ERG, which in turn led to deregulated expression of ERG, compromising the function of ERG either by deletion of part of the gene, or by the expression of another form of ERG (ERGalt). In both cases, loss of activity was observed for the ERG transcription factor, which led to leukaemia.
Co-author Dr Li Ding, assistant director of The McDonnell Genome Institute and director of computational biology in the Division of Oncology at Washington University School of Medicine in St Louis, noted: “Our data reveal that a genetic rearrangement of DUX4 is present in all cases for patients with the distinct gene expression profile identified in our study. The genetic rearrangement of DUX4 is a clonal event that is acquired early in the development of leukaemia.”
Co-author Dr Stephen Hunger, chief of the Division of Oncology at the Children’s Hospital of Philadelphia, added that the genetic defects underlying this relatively common subset of B-ALL were not fully understood before discovery of the DUX4 abnormalities.
“These results underscore that there is still more to be learned about the genetic changes in ALL, and that this knowledge can help refine treatment for patients,” he said.
The researchers hope identification of the relationships between the two transcription factors will lead to new diagnostic tests for patients.
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