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Molecular Features of ALL Subtype Refined Through Pediatric Cancer Genome Project Analysis

NEW YORK (GenomeWeb) – A new study suggests that a subset of pediatric B-cell acute lymphoblastic leukemia (ALL) cases are marked by misregulation of the transcription factor genes DUX4 and ERG.

Investigators from the St. Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project used a combination of genome sequencing, RNA sequencing, array-based expression profiling, and chromatin immunoprecipitation sequencing to characterize more than 1,900 B-cell ALL cases involving children, adolescents, or young adults. Their findings, published today in Nature Genetics, revealed recurrent rearrangements of DUX4 that were associated with ERG loss-of-function due to unusual isoform expression or deletion.

"Our data reveal that a genetic rearrangement of DUX4 is present in all cases for patients with the distinct gene expression profile that was identified in our study. The genetic rearrangement of DUX4 is a clonal event that is acquired early in the development of leukemia," co-author Li Ding, assistant director of The McDonnell Genome Institute, said in a statement.

Past studies of B-cell ALL have uncovered examples of tumors containing DUX4 fusions or deletions affecting ERG, a transcription factor-coding gene involved in blood cell differentiation and regulation that has also been implicated in other conditions such as acute myeloid leukemia and prostate cancer. But a complete picture of this potential B-cell ALL subtype remains unresolved.

To get a closer look at the potential ERG alteration-containing subtype, the researchers focused on samples from 1,347 children with the disease, 395 adolescents between the ages of 16 and 20, and 171 young adults ranging in age from 21 to 39. They profiled expression patterns for all of the participants using microarrays, and performed genome, exome, and/or transcriptome sequencing on a few dozen tumors.

In the process, the researchers found that 7.6 percent of the B-cell ALL cases clustered together based on their gene expression patterns, including almost one-tenth of the adolescent cases and pediatric cases deemed high risk. When they took a closer look at molecular features in this potential subtype, the investigators identified ERG deletions in more than half of the cases and DUX4 rearrangement across all of the samples sharing the expression signature.

The team noted that samples from the DUX4-ERG altered subtype were prone to mutations affecting other transcription factors, as well as transcriptional shifts leading to the expression of unusual ERG transcripts in some tumors without ERG deletions.

The researchers suspected that the DUX4 rearrangement and the altered ERG regulation found in the tumors was not a coincidence, but might represent important contributors to B-cell ALL development — a hypothesis supported by ChIP-seq experiments demonstrating binding between RNX4 and ERG, DUX4 over-expression experiments done in cord blood hematopoietic cells, and other follow-up analyses.

"These findings have important clinical implications, as DUX4/ERG ALL is associated with favorable outcome, irrespective of the presence of concomitant genetic alterations otherwise associated with poor outcomes in other contexts," the authors wrote. They added, however, that "DUX4 rearrangement is not evident on karyotypic analysis, and is challenging to identify on analysis of genome and RNA-sequencing data."