Journal
NATURE GENETICS
Volume 48, Issue 12, Pages 1481-1489Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3691
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Funding
- American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital
- Stand Up to Cancer Innovative Research Grant
- St. Baldrick's Foundation Scholar Award
- St. Baldrick's Consortium Award
- Leukemia and Lymphoma Society Specialized Center of Research grant
- Lady Tata Memorial Trust Award
- Leukemia and Lymphoma Society Special Fellow Award
- Alex's Lemonade Stand Foundation Young Investigator Awards
- American Society of Hematology Scholar Awards
- Dutch Cancer Society Fellowship [KUN2012-5366]
- St. Luke's Life Science Institute grant
- National Cancer Institute [P30 CA021765, U10 CA180820, CA180827, CA196172, U10 CA180861, U24 CA196171, CA145707, U01 CA157937, R00 CA188293, U10 CA98543, U10 CA98413, U24 CA114766]
- National Institute of General Medical Sciences [P50 GM115279]
- National Cancer Institute, US National Institutes of Health [HHSN261200800001E]
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Chromosomal rearrangements deregulating hematopoietic transcription factors are common in acute lymphoblastic leukemia (ALL). Here we show that deregulation of the homeobox transcription factor gene DUX4 and the ETS transcription factor gene ERG is a hallmark of a subtype of B-progenitor ALL that comprises up to 7% of B-ALL. DUX4 rearrangement and overexpression was present in all cases and was accompanied by transcriptional deregulation of ERG, expression of a novel ERG isoform, ERGalt, and frequent ERG deletion. ERGalt uses a non-canonical first exon whose transcription was initiated by DUX4 binding. ERGalt retains the DNA-binding and transactivation domains of ERG, but it inhibits wild-type ERG transcriptional activity and is transforming. These results illustrate a unique paradigm of transcription factor deregulation in leukemia in which DUX4 deregulation results in loss of function of ERG, either by deletion or induced expression of an isoform that is a dominant-negative inhibitor of wild-type ERG function.
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