Abstract
ERG deregulation by deletion or expression of a dominant-negative transcript drives a subset of B-ALL.
Major finding: ERG deregulation by deletion or expression of a dominant-negative transcript drives a subset of B-ALL.
Mechanism: DUX4 upregulation and binding at the ERG locus promotes expression of an alternative ERG transcript.
Impact: The identification of DUX4/ERG B-ALL may improve patient risk stratification and guide treatment.
The genetic underpinnings of many cases of B-progenitor acute lymphoblastic leukemia (B-ALL) have not been determined. A subset of cases displays a characteristic gene expression profile and frequent deletion of ERG, which encodes an ETS-family transcription factor essential for hematopoietic differentiation. To further characterize this and other B-ALL subtypes, Zhang and colleagues performed expression profiling and DNA copy-number analysis on 1,913 patients with B-ALL combined with whole-genome, whole-exome, and RNA sequencing in a subset. A distinct gene expression profile was observed in 141 (7.6%) cases, and 85 (55.6%) of those had focal deletions of ERG that were not present in other cases. Further, in all cases with transcriptome data available, the gene encoding the double-homeobox transcription factor DUX4 was upregulated by a chromosomal rearrangement placing DUX4 under the control of the IGH enhancer. Transcriptional deregulation of ERG was observed in all DUX4-rearranged cases with identification of a noncanonical aberrant ERG transcript (ERGalt) that lacked the N-terminus and instead was initiated from an alternative exon 6 fused to exon 7 and the downstream exons, resulting in a truncated protein. Analysis of data from the Pediatric Cancer Genome Project showed that expression of aberrant ERG transcripts was rare in other ALL subtypes and other tumor types. DUX4 bound at the alternative exon 6 of ERG and promoted expression of ERGalt, providing a mechanism by which DUX4 rearrangement may promote ERG deregulation. Functionally, ERGalt retained DNA binding activity and acted as a competitive inhibitor of wild-type ERG, and mice transplanted with cells expressing ERGalt developed pre-B cell leukemia, suggesting that it promotes lymphoid leukemogenesis. The identification and genomic characterization of a B-ALL subtype characterized by DUX4 rearrangement and ERG deregulation may allow for improved risk stratification and guide therapy in patients with B-ALL, as patients with this form of leukemia have an excellent prognosis.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.
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