Dataset Information

Deregulation of DUX4 and ERG in acute lymphoblastic leukemia.

ABSTRACT: 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.

SUBMITTER: Zhang J

PROVIDER: S-EPMC5144107 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Publications

Deregulation of DUX4 and ERG in acute lymphoblastic leukemia.

Zhang Jinghui J McCastlain Kelly K Yoshihara Hiroki H Xu Beisi B Chang Yunchao Y Churchman Michelle L ML Wu Gang G Li Yongjin Y Wei Lei L Iacobucci Ilaria I Liu Yu Y Qu Chunxu C Wen Ji J Edmonson Michael M Payne-Turner Debbie D Kaufmann Kerstin B KB Takayanagi Shin-Ichiro SI Wienholds Erno E Waanders Esmé E Ntziachristos Panagiotis P Bakogianni Sofia S Wang Jingjing J Aifantis Iannis I Roberts Kathryn G KG Ma Jing J Song Guangchun G Easton John J Mulder Heather L HL Chen Xiang X Newman Scott S Ma Xiaotu X Rusch Michael M Gupta Pankaj P Boggs Kristy K Vadodaria Bhavin B Dalton James J Liu Yanling Y Valentine Marcus L ML Ding Li L Lu Charles C Fulton Robert S RS Fulton Lucinda L Tabib Yashodhan Y Ochoa Kerri K Devidas Meenakshi M Pei Deqing D Cheng Cheng C Yang Jun J Evans William E WE Relling Mary V MV Pui Ching-Hon CH Jeha Sima S Harvey Richard C RC Chen I-Ming L IL Willman Cheryl L CL Marcucci Guido G Bloomfield Clara D CD Kohlschmidt Jessica J Mrózek Krzysztof K Paietta Elisabeth E Tallman Martin S MS Stock Wendy W Foster Matthew C MC Racevskis Janis J Rowe Jacob M JM Luger Selina S Kornblau Steven M SM Shurtleff Sheila A SA Raimondi Susana C SC Mardis Elaine R ER Wilson Richard K RK Dick John E JE Hunger Stephen P SP Loh Mignon L ML Downing James R JR Mullighan Charles G CG

Nature genetics 20161024 12

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 fre ...[more]

PMID: 27776115

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Project description:ERG-deletions occur recurrently in acute lymphoblastic leukemia, especially in the DUX4-rearranged subtype. The ERG-deletion was shown to positively impact prognosis of patients with IKZF1-deletion and its presence precludes assignment into IKZF1 plus group, a novel high-risk category on AIEOP-BFM ALL trials. We analyzed the impact of different methods on ERG-deletion detection rate, evaluated ERG-deletion as a potential marker for DUX4-rearranged leukemia, studied its associations with molecular and clinical characteristics within this leukemia subtype, and analyzed its clonality. Using single-nucleotide-polymorphism array, genomic polymerase chain reaction (PCR) and amplicon-sequencing we found ERG-deletion in 34% (16 of 47), 66% (33 of 50) and 78% (39 of 50) of DUX4-rearranged leukemia, respectively. False negativity of ERG-deletion by single-nucleotide-polymorphism array caused IKZF1 plus misclassification in 5 patients. No ERG-deletion was found outside the DUX4-rearranged cases. Within DUX4-rearranged leukemia, the ERG-deletion was associated with higher total number of copy-number aberrations, and, importantly, the ERG-deletion positivity by PCR was associated with better outcome [5-year event-free survival (EFS), ERG-deletion-positive 93% vs. ERG-deletion-negative 68%, P=0.022; 5-year overall survival (OS), ERG-deletion-positive 97% vs. ERG-deletion-negative 75%, P=0.029]. Ultra-deep amplicon-sequencing revealed distinct co-existing ERG-deletions in 22 of 24 patients. In conclusion, our data demonstrate inadequate sensitivity of single-nucleotide-polymorphism array for ERG-deletion detection, unacceptable for proper IKZF1 plus classification. Even using more sensitive methods (PCR/amplicon-sequencing) for its detection, ERG-deletion is absent in 22-34% of DUX4-rearranged leukemia and does not represent an adequately sensitive marker of this leukemia subtype. Importantly, the ERG-deletion potentially stratifies the DUX4-rearranged leukemia into biologically/clinically distinct subsets. Frequent polyclonal pattern of ERG-deletions shows that late origin of this lesion is more common than has been previously described.

Dataset Information

Deregulation of DUX4 and ERG in acute lymphoblastic leukemia.

Publications

Deregulation of DUX4 and ERG in acute lymphoblastic leukemia.

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