Publication

Deregulation of DUX4 and ERG in acute lymphoblastic leukemia.

Nat Genet. 2016 Oct 24. doi: 10.1038/ng.3691. [Epub ahead of print]

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.

Authors

Zhang J1, McCastlain K2, Yoshihara H2, Xu B1, Chang Y2, Churchman ML2, Wu G1, Li Y1, Wei L1,2, Iacobucci I2, Liu Y1, Qu C1, Wen J1, Edmonson M1, Payne-Turner D2, Kaufmann KB3, Takayanagi SI3,4, Wienholds E3, Waanders E2,5, Ntziachristos P6, Bakogianni S6, Wang J6, Aifantis I6,7, Roberts KG2, Ma J2, Song G2, Easton J1, Mulder HL1, Chen X1, Newman S1, Ma X1, Rusch M1, Gupta P1, Boggs K1, Vadodaria B1, Dalton J2, Liu Y2, Valentine ML8, Ding L9, Lu C9, Fulton RS9, Fulton L9, Tabib Y9, Ochoa K9, Devidas M10, Pei D11, Cheng C11, Yang J12, Evans WE12, Relling MV12, Pui CH13, Jeha S13, Harvey RC14, Chen IL14, Willman CL14, Marcucci G15, Bloomfield CD16, Kohlschmidt J16, Mrózek K16, Paietta E17, Tallman MS18, Stock W19, Foster MC20, Racevskis J21, Rowe JM22, Luger S23, Kornblau SM24, Shurtleff SA2, Raimondi SC2, Mardis ER9, Wilson RK9, Dick JE3, Hunger SP25, Loh ML26, Downing JR2, Mullighan CG2; St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project.