The genetic changes of the most common cancer subtypes B-ALL

The International Study Group from St. Jude Children's Research Hospital, the University of Washington Pediatric Cancer Genome Project (PCGP) and the Children's Oncology Group (COG) identified the genetic changes of the most common cancer subtypes B-precursor acute lymphoblastic leukemia (B-ALL) through recombinant dog proteins. In this disease, two transcription factors, DUX4 and ERG, are genetically altered, and these proteins closely control the activity of other key genes in human blood cells. The results of the study were published in the October 24 issue of Nature Genetics.

Scientists have discovered a unique mechanism that can explain how transcription factors contribute to the development of leukemia. "Our work reveals that there are a series of molecular events in B-ALL that involve the interaction of two transcription factors," said Charles Mullighan, author of the article, and author of St Jude's Pathology.

Transcription factor is a protein that binds to a particular DNA sequence and regulates the expression of genetic information from DNA to mRNA. ChIP sequencing, a method that allows researchers to analyze how proteins interact with DNA, and it is the key to revealing the relationship between two transcription factors. Sequencing studies revealed that the rearrangement of the transcription factor gene, DUX4, occurred in all B-ALL cases, resulting in high levels of DUX4 expression. DUX4 binds to the gene of the transcription factor ERG, resulting in downregulation of ERG expression. Downregulation of ERG expression impairs ERG function by deletion of part of the gene or by expression of another form of ERG (ERGalt). In both cases, loss of ERG transcription factor activity was observed, which resulted in leukemia.

"The discovery of the relationship between DUX4 fusion and aberrant ERG isoforms uses a novel computational approach developed by us that combines whole-genome sequencing, RNA-seq and ChIP," said Jinghui Zhang, PhD, Department of Computational Biology, St. Jude's first author. "The genomic landscape of B-ALL subtypes can also be visualized using ProteinPaint (pecan.stjude.org), a powerful interactive tool developed by St. Jude and it is used to examine pediatric Cancer mutations and gene expression.

"Our data show that DUX4 gene rearrangement is present in all patients with different gene expression profiles," said Li Ding, co-author of the paper and assistant director of the McDonnell Genome Research Institute and director of computational biology at the University Of Washington School Of Medicine in St. Louis. The gene rearrangements are cloned in the early stages of leukemia.

Stephen Hunger, co-author of the paper said that genetic defects in this relatively common B-ALL subtype were not fully understood until DUX4 abnormalities were found. "These results underscore the need for more knowledge of genetic variation in ALL, which can help to improve patient care," he said.

The researchers hope that the determination of the relationship between the two transcription factors will lead to the emergence of new diagnostic tests. Even with other deleterious genetic mutations, DUX4 / ERG ALL were associated with a favorable outcome. Currently, only transcriptome or genome sequencing helps to identify DUX4 rearrangements. "Other detection methods, such as fluorescent hybridization or microscopic examination of chromosomes (karyotype analysis), are not sufficient to identify genetic changes in DUX4", scientists said. Flarebio offers recombinant proteins such as recombinant Cdh10 at competitive prices.