Deregulation of DUX4 and ERG in acute lymphoblastic leukemia

Charles Mullighan, Jinghui Zhang and colleagues characterize a subtype of B-progenitor acute lymphoblastic leukemia with deregulated DUX4 and ERG . They find that aberrant DUX4 activation results in loss of ERG function, either through deletion or by the induction a novel transforming ERG isoform, E...

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Vydáno v:	Nature genetics Ročník 48; číslo 12; s. 1481 - 1489
Hlavní autoři:	Zhang, Jinghui, McCastlain, Kelly, Yoshihara, Hiroki, Xu, Beisi, Chang, Yunchao, Churchman, Michelle L, Wu, Gang, Li, Yongjin, Wei, Lei, Iacobucci, Ilaria, Liu, Yu, Qu, Chunxu, Wen, Ji, Edmonson, Michael, Payne-Turner, Debbie, Kaufmann, Kerstin B, Takayanagi, Shin-ichiro, Wienholds, Erno, Waanders, Esmé, Ntziachristos, Panagiotis, Bakogianni, Sofia, Wang, Jingjing, Aifantis, Iannis, Roberts, Kathryn G, Ma, Jing, Song, Guangchun, Easton, John, Mulder, Heather L, Chen, Xiang, Newman, Scott, Ma, Xiaotu, Rusch, Michael, Gupta, Pankaj, Boggs, Kristy, Vadodaria, Bhavin, Dalton, James, Liu, Yanling, Valentine, Marcus L, Ding, Li, Lu, Charles, Fulton, Robert S, Fulton, Lucinda, Tabib, Yashodhan, Ochoa, Kerri, Devidas, Meenakshi, Pei, Deqing, Cheng, Cheng, Yang, Jun, Evans, William E, Relling, Mary V, Pui, Ching-Hon, Jeha, Sima, Harvey, Richard C, Chen, I-Ming L, Willman, Cheryl L, Marcucci, Guido, Bloomfield, Clara D, Kohlschmidt, Jessica, Mrózek, Krzysztof, Paietta, Elisabeth, Tallman, Martin S, Stock, Wendy, Foster, Matthew C, Racevskis, Janis, Rowe, Jacob M, Luger, Selina, Kornblau, Steven M, Shurtleff, Sheila A, Raimondi, Susana C, Mardis, Elaine R, Wilson, Richard K, Dick, John E, Hunger, Stephen P, Loh, Mignon L, Downing, James R, Mullighan, Charles G
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	New York Nature Publishing Group US 01.12.2016 Nature Publishing Group
Témata:	45 45/23 631/114/2785/2302 631/208/200 631/208/212/2019 631/67/1990/283/2125 692/699/67/1990/283/2125 Acute lymphocytic leukemia Adolescent Adult Agriculture Animal Genetics and Genomics Biomedicine Cancer Cancer Research Cell cycle Cell Transformation, Neoplastic - genetics Cell Transformation, Neoplastic - pathology Children & youth Deregulation DNA binding proteins Gene Deletion Gene expression Gene Expression Profiling Gene Expression Regulation, Neoplastic Gene Function Gene Rearrangement Genes Genetic aspects Genomes Grants Homeodomain Proteins - genetics Hospitals Human Genetics Humans Leukemia Lymphoma Mutation Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology Protein Isoforms Transcription (Genetics) Transcription factors Transcriptional Regulator ERG - genetics Young Adult
ISSN:	1061-4036, 1546-1718, 1546-1718
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Shrnutí:	Charles Mullighan, Jinghui Zhang and colleagues characterize a subtype of B-progenitor acute lymphoblastic leukemia with deregulated DUX4 and ERG . They find that aberrant DUX4 activation results in loss of ERG function, either through deletion or by the induction a novel transforming ERG isoform, ERGalt, that inhibits wild-type ERG activity. 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.
Bibliografie:	SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23 Present address: Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/ng.3691