Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers

Zhang, Xiaoyang; Choi, Peter S.; Francis, Joshua M.; Imieliński, Marcin; Watanabe, Hideo; Cherniack, Andrew D.; Meyerson, Matthew

doi:10.1038/ng.3470

Cited by 309 publications

(309 citation statements)

References 54 publications

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“…This region interacts with the MYC promoter in small lymphocytic lymphoma and mantle cell lymphoma, and also leads to MYC transcriptional activation in Epstein-Barr-transformed lymphoblastoid cells as a result of Epstein-Barr virus nuclear antigen 2 binding (52,62). The focal recurrent duplications of this locus observed in CLL (7,53), analogous to what is observed in other malignancies in which CN gains affect the tissue-specific enhancers involved in MYC expression (50,63,64), suggest that the gain of context-specific superenhancers represents a common mechanism for up-regulating MYC expression in distinct tumor types. However, the detection of this superenhancer cluster also in CLL cases devoid of ICN1 expression (Fig.…”

Section: Notch1mentioning

confidence: 64%

Common nonmutationalNOTCH1activation in chronic lymphocytic leukemia

Fabbri

Holmes

Viganotti

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

112

160

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Activating mutations of NOTCH1 (a well-known oncogene in T-cell acute lymphoblastic leukemia) are present in ∼4-13% of chronic lymphocytic leukemia (CLL) cases, where they are associated with disease progression and chemorefractoriness. However, the specific role of NOTCH1 in leukemogenesis remains to be established. Here, we report that the active intracellular portion of NOTCH1 (ICN1) is detectable in ∼50% of peripheral blood CLL cases lacking gene mutations. We identify a "NOTCH1 gene-expression signature" in CLL cells, and show that this signature is significantly enriched in primary CLL cases expressing ICN1, independent of NOTCH1 mutation. NOTCH1 target genes include key regulators of B-cell proliferation, survival, and signal transduction. In particular, we show that NOTCH1 transactivates MYC via binding to B-cell-specific regulatory elements, thus implicating this oncogene in CLL development. These results significantly extend the role of NOTCH1 in CLL pathogenesis, and have direct implications for specific therapeutic targeting. chronic lymphocytic leukemia | NOTCH1 | transcriptional network

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Section: Notch1mentioning

confidence: 64%

Common nonmutationalNOTCH1activation in chronic lymphocytic leukemia

Fabbri

Holmes

Viganotti

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

112

160

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“…sgRNAs were cloned into plenti-Guide-Puro (Addgene, 52963). Lentivirus expressing dCAS9-KRAB (Gift from Matthew Meyerson Lab) 28 were used to infect EP1-NS, following which cells were selected 48h with 10 μg/ml blasticidin. These cells were then infected with selected lentiGuide-Puro sgRNA constructs and selected 48h with 1 μg/ml puromycin.…”

Section: Methodsmentioning

confidence: 99%

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

Mack¹,

Pajtler

Chávez

et al. 2017

Nature

187

218

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SUMMARY Genomic sequencing has driven precision-based oncology therapy; however, genetic drivers remain unknown or non-targetable for many malignancies, demanding alternative approaches to identify therapeutic leads. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated based on anatomical location – supratentorial region (ST) or posterior fossa (PF) – and further divided into distinct molecular subgroups that reflect differences in age of onset, gender predominance, and response to therapy1–3. The most common and aggressive subgroup, Posterior Fossa Ependymoma Group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations2. Conversely, Posterior Fossa Ependymoma Group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses yet favourable clinical outcomes1,3. Greater than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NFκB subunit RELA (ST-EPN-RELA), and less frequently involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1).1,3,4 Subependymomas, a distinct histologic variant, can also be found within the ST and PF compartments accounting for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE, respectively1. Here, we mapped active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts with the goal of identifying essential super enhancer associated genes on which tumour cells were dependent. Enhancer regions revealed putative oncogenes, molecular targets, and pathways, which when subjected to small molecule inhibitor or shRNA treatment, diminished proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers recalcitrant to therapeutic development because of their lack of known genetic drivers.

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“…Data on the effect of the deletion on the cancer phenotype are not available for all of the studies. However, the effect on cancer-associated features such as proliferation has been documented for deletion of some enhancer elements, strengthening their potential as targets for cancer chemo prevention and therapy 51,93,131,132 (TABLE 1).…”

Section: Bet-bromodomain Proteinmentioning

confidence: 97%

“…These non-coding amplifications seem to be under positive selection, based on the observations that specific amplifications and copy number changes in these regions accumulate over time 90 , and that the chromosome region carrying an inherited risk allele affecting an enhancer can be preferentially amplified 91,92 . Furthermore, non-coding amplifications in tumour cells can specifically affect the enhancers of known oncogenes, such as MYC 93,94 .…”

Section: Somatic Non-coding Mutations In Enhancersmentioning

confidence: 99%

The role of enhancers in cancer

2016

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Enhancer elements function as the logic gates of the genetic regulatory circuitry. One of their most important functions is the integration of extracellular signals with intracellular cell fate information to generate cell type-specific transcriptional responses. Mutations occurring in cancer often misregulate enhancers that normally control the signal-dependent expression of growth-related genes. This misregulation can result from trans-acting mechanisms, such as activation of the transcription factors or epigenetic regulators that control enhancer activity, or can be caused in cis by direct mutations that alter the activity of the enhancer or its target gene specificity. These processes can generate tumour type-specific super-enhancers and establish a 'locked' gene regulatory state that drives the uncontrolled proliferation of cancer cells. Here, we review the role of enhancers in cancer, and their potential as therapeutic targets.

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Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers

Cited by 309 publications

References 54 publications

Common nonmutationalNOTCH1activation in chronic lymphocytic leukemia

Common nonmutationalNOTCH1activation in chronic lymphocytic leukemia

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

The role of enhancers in cancer

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