Deregulation of DUX4 and ERG in acute lymphoblastic leukemia

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 N.; 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; Li, Ding; Lu, Charles; Fulton, Robert S.; Fulton, Lucinda L.; Tabib, Yashodhan; Ochoa, Kerri; Devidas, Meenakshi; Pei, Deqing; Cheng, Cheng; Yang, Jun J.; 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 M.; Kornblau, Steven M.; Shurtleff, Sheila; Raimondi, Susana C.; Mardis, Elaine R.; Wilson, Richard K.; Dick, John E.; Hunger, Stephen P.; Loh, Mignon L.; Downing, James R.; Mullighan, Charles G.

doi:10.1038/ng.3691

Cited by 262 publications

(324 citation statements)

References 56 publications

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“…Recurrent IGH ‐ DUX4 ( double homeobox 4 ) fusions, resulting in DUX4 overexpression and a unique gene expression signature, were very recently reported in up to 7% of childhood B‐ALL cases. DUX4 rearrangement results in loss of function of ERG ( ETS‐related gene ) via intragenic deletion or via induction of a dominant‐negative isoform that inhibits wild‐type ERG (Zhang et al , ). ERG‐DUX4 fusions have also been reported (Lilljebjorn et al , ).…”

Section: B‐cell Acute Lymphoblastic Leukaemiamentioning

confidence: 99%

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Genomic characterization of paediatric acute lymphoblastic leukaemia: an opportunity for precision medicine therapeutics

Tasian

Hunger

2016

Br J Haematol

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Major advances in genetic and epigenetic profiling of acute lymphoblastic leukaemia (ALL) have enhanced the understanding of key biological subsets of de novo and relapsed ALL, which has led to improved risk stratification of patients. These achievements have further defined critical leukaemia-associated pathways and somatic alterations that may be preferentially sensitive to treatment with kinase inhibitors, epigenetic therapy or other novel agents. Therapeutic success in childhood ALL currently relies upon refined risk stratification of patients based on (1) underlying biological and clinical characteristics and (2) depth of initial treatment response with appropriate modulation of chemotherapy intensity. This review describes the current mutational landscape of childhood ALL and discusses opportunities for substantial improvements in survival with implementation of molecularly targeted therapies.

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Section: B‐cell Acute Lymphoblastic Leukaemiamentioning

confidence: 99%

“…ERG‐DUX4 fusions have also been reported (Lilljebjorn et al , ). Despite frequent concomitant IKZF1 deletions, patients with DUX4 rearrangements appear to have excellent clinical prognoses with standard chemotherapy treatment (Clappier et al , ; Lilljebjorn et al , ; Yasuda et al , ; Zhang et al , ).…”

Section: B‐cell Acute Lymphoblastic Leukaemiamentioning

confidence: 99%

Genomic characterization of paediatric acute lymphoblastic leukaemia: an opportunity for precision medicine therapeutics

Tasian

Hunger

2016

Br J Haematol

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“…The majority of studies have shown that IKZF1 alterations are associated with poor outcome, both in ALL cohorts comprising multiple subtypes, and in BCR-ABL1 ALL, including cases treated with TKI (19, 21–36). An exception is a subtype of ALL characterized by deregulation of the double homeobox gene DUX4 and the ETS family transcription factor ERG , in which IKZF1 alterations are common but not associated with poor outcome (37, 38). …”

Section: A Central Role For Ikzf1 Alterations In the Pathogenesis Ofmentioning

confidence: 99%

Ikaros: Exploiting and targeting the hematopoietic stem cell niche in B-progenitor acute lymphoblastic leukemia

Churchman

Mullighan

2017

Experimental Hematology

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Genetic alterations of IKZF1 encoding the lymphoid transcription factor IKAROS are a hallmark of high risk B-progenitor ALL such as BCR-ABL1 positive (Ph+) and Ph-like ALL, and are associated with poor outcome, even in the era of contemporary chemotherapy incorporating tyrosine kinase inhibitors in the treatment of Ph+ ALL. Recent experimental mouse modeling of B-progenitor ALL has shown that IKZF1 alterations have multiple effects, including arresting differentiating, skewing lineage of leukemia from myeloid to lymphoid, and in Ph+ leukemia, conferring resistance to TKI therapy without abrogating ABL1 inhibition. These effects are in part mediated by acquisition of an aberrant hematopoietic stem cell like program accompanied by induction of cell surface expression of stem cell and adhesion molecules that mediate extravascular invasion and residence in the niche, and activation of integrin signaling pathways. These effects can be exploited therapeutically using several approaches. IKZF1 alterations also result in upregulation of RXRA that encodes part of the heterodimeric retinoic acid X receptor. Rexinoids, a synthetic class of retinoids that specifically bind to retinoid “X” receptors, such as bexarotene potently reverse aberrant adhesion and niche mislocalization in vivo, and induce differentiation and cell cycle arrest. Focal adhesion kinase inhibitors block the downstream integrin-mediated signaling, and also reverse adhesion and niche mislocalization. Both agents act synergistically with TKI to prolong survival of Ph+ ALL in mouse and human xenograft model, with long term remission induced by FAK inhibitors. Thus, these findings provide important new conceptual insights into the mechanisms by which IKZF1 alterations result in drug resistance, and indicate that therapeutic strategies directed against the pathways deregulated by mutation, rather than attempting to restore IKZF1 expression directly, represent promising therapeutic approaches in this disease.

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“…ERG-wt expression was not altered in relation to ERG status but 46% of ERG-related patients expressed a short ERG isoform, supposedly the ERGalt protein recently described in another ERG-related cohort [6] and shown to inhibit wild type ERG transcriptional activity.…”

Section: Discussionmentioning

confidence: 91%

High expression of miR-125b-2 and SNORD116 noncoding RNA clusters characterize ERG-related B cell precursor acute lymphoblastic leukemia

et al. 2017

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ERG-related leukemia is a B cell precursor acute lymphoblastic leukemia (BCP ALL) subtype characterized by aberrant expression of DUX4 and ERG transcription factors, and highly recurrent ERG intragenic deletions. ERG-related patients have remarkably favorable outcome despite a high incidence of inauspicious IKZF1 aberrations.We describe clinical and genomic features of the ERG-related cases in an unselected cohort of B-other BCP ALL pediatric patients enrolled in the AIEOP ALL 2000 therapeutic protocol. We report a small noncoding RNA signature specific of ERG-related group, with up-regulation of miR-125b-2 cluster on chromosome 21 and several snoRNAs in the Prader-Willi locus at 15q11.2, including the orphan SNORD116 cluster.

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Deregulation of DUX4 and ERG in acute lymphoblastic leukemia

Cited by 262 publications

References 56 publications

Genomic characterization of paediatric acute lymphoblastic leukaemia: an opportunity for precision medicine therapeutics

Genomic characterization of paediatric acute lymphoblastic leukaemia: an opportunity for precision medicine therapeutics

Ikaros: Exploiting and targeting the hematopoietic stem cell niche in B-progenitor acute lymphoblastic leukemia

High expression of miR-125b-2 and SNORD116 noncoding RNA clusters characterize ERG-related B cell precursor acute lymphoblastic leukemia

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