Deregulation of DUX4 and ERG in acute lymphoblastic leukemia.

Zhang J, McCastlain K, Yoshihara H, Xu B, Chang Y, Churchman ML, Wu G, Li Y, Wei L, Iacobucci I, Liu Y, Qu C, Wen J, Edmonson M, Payne-Turner D, Kaufmann KB, Takayanagi SI, Wienholds E, Waanders E, Ntziachristos P, Bakogianni S, Wang J, Aifantis I, Roberts KG, Ma J, Song G, Easton J, Mulder HL, Chen X, Newman S, Ma X, Rusch M, Gupta P, Boggs K, Vadodaria B, Dalton J, Liu Y, Valentine ML, Ding L, Lu C, Fulton RS, Fulton L, Tabib Y, Ochoa K, Devidas M, Pei D, Cheng C, Yang J, Evans WE, Relling MV, Pui CH, Jeha S, Harvey RC, Chen IL, Willman CL, Marcucci G, Bloomfield CD, Kohlschmidt J, Mrózek K, Paietta E, Tallman MS, Stock W, Foster MC, Racevskis J, Rowe JM, Luger S, Kornblau SM, Shurtleff SA, Raimondi SC, Mardis ER, Wilson RK, Dick JE, Hunger SP, Loh ML, Downing JR, Mullighan CG, St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project
Nat Genet 48 1481-1489 12/01/2016

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.

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