BET Bromodomain Inhibition Suppresses the Function of Hematopoietic Transcription Factors in Acute Myeloid Leukemia

Roe, Jae Seok; Mercan, Fatih; Rivera, Keith; Pappin, Darryl; Vakoc, Christopher R.

doi:10.1016/j.molcel.2015.04.011

Cited by 296 publications

(355 citation statements)

References 54 publications

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“…Cell type-specific distribution of BRD4 is accomplished by TF recruitment to their enhancers (41). Our study showed that PAX3-FOXO1 can direct de novo recruitment of BRD4 to specific chromatin sites when introduced into human fibroblasts, accompanied by opening of chromatin and acetylation of H3K27 at enhancers proximal to key RMS genes.…”

Section: Discussionmentioning

confidence: 69%

PAX3–FOXO1 Establishes Myogenic Super Enhancers and Confers BET Bromodomain Vulnerability

et al. 2017

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Alveolar rhabdomyosarcoma is a life-threatening myogenic cancer of children and adolescent young adults, driven primarily by the chimeric transcription factor PAX3-FOXO1. The mechanisms by which PAX3-FOXO1 dysregulates chromatin are unknown. We fi nd PAX3-FOXO1 reprograms the cis -regulatory landscape by inducing de novo super enhancers. PAX3-FOXO1 uses super enhancers to set up autoregulatory loops in collaboration with the master transcription factors MYOG, MYOD, and MYCN. This myogenic super enhancer circuitry is consistent across cell lines and primary tumors. Cells harboring the fusion gene are selectively sensitive to small-molecule inhibition of protein targets induced by, or bound to, PAX3-FOXO1-occupied super enhancers. Furthermore, PAX3-FOXO1 recruits and requires the BET bromodomain protein BRD4 to function at super enhancers, resulting in a complete dependence on BRD4 and a signifi cant susceptibility to BRD inhibition. These results yield insights into the epigenetic functions of PAX3-FOXO1 and reveal a specifi c vulnerability that can be exploited for precision therapy.SIGNIFICANCE: PAX3-FOXO1 drives pediatric fusion-positive rhabdomyosarcoma, and its chromatinlevel functions are critical to understanding its oncogenic activity. We fi nd that PAX3-FOXO1 establishes a myoblastic super enhancer landscape and creates a profound subtype-unique dependence on BET bromodomains, the inhibition of which ablates PAX3-FOXO1 function, providing a mechanistic rationale for exploring BET inhibitors for patients bearing PAX-fusion rhabdomyosarcoma. Cancer Discov; 7(8);

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Section: Discussionmentioning

confidence: 69%

PAX3–FOXO1 Establishes Myogenic Super Enhancers and Confers BET Bromodomain Vulnerability

et al. 2017

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“…We also found that p300 helps to recruit BRD4 to the BATF promoter region. In fact, recent studies have demonstrated that BRD4 and p300 form a complex to transcriptionally activate several other genes such as MYC and FOS (50,51). Our studies of pharmacological modulation of BET and p300 point to an acetylation-dependent signaling mechanism, since JQ1 directly inhibits BET protein binding to acetylated lysine residues in chromatin and C646 inhibits the catalytic acetyltransferase activity of p300.…”

Section: Discussionmentioning

confidence: 73%

BET bromodomain inhibition enhances T cell persistence and function in adoptive immunotherapy models

Kagoya¹,

Nakatsugawa²,

Yamashita³

et al. 2016

Journal of Clinical Investigation

176

159

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“…The latter are known to mediate long-range dysregulation of key oncogenes in hematologic cancers 52 and to coordinate activity of key hematopoietic transcription factors in leukemia. 66 Alternatively, disruption of BRD4 interaction with transcription and elongation factors (eg, polymerase II, positive transcription elongation factor b, Mediator, and Activator) may be part of the mechanism by which JQ1 inhibits lincRNA-3q expression. Finally, intrinsic histone acetylase activity of BRD4 itself may play a role.…”

Section: Discussionmentioning

confidence: 99%

Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms

Emadali

Hoghoughi

Duley

et al. 2016

Blood

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Key Points• NR3C1 haploinsufficiency is found in patients with a plasmacytoid dendritic cell neoplasm characterized by very poor clinical outcome.• Overexpression of lincRNA3q is a consistent feature of malignant cells in these patients and can be abrogated by BET protein inhibition.Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive leukemia for which knowledge on disease mechanisms and effective therapies are currently lacking. Only a handful of recurring genetic mutations have been identified and none is specific to BPDCN. In this study, through molecular cloning in an index case that presented a balanced t(3;5)(q21;q31) and molecular cytogenetic analyses in a further 46 cases, we identify monoallelic deletion of NR3C1 (5q31), encoding the glucocorticoid receptor (GCR), in 13 of 47 (28%) BPDCN patients. Targeted deep sequencing in 36 BPDCN cases, including 10 with NR3C1 deletion, did not reveal NR3C1 point mutations or indels. Haploinsufficiency for NR3C1 defined a subset of BPDCN with lowered GCR expression and extremely poor overall survival (P 5 .0006). Consistent with a role for GCR in tumor suppression, functional analyses coupled with gene expression profiling identified corticoresistance and loss-of-EZH2 function as major downstream consequences of NR3C1 deletion in BPDCN. Subsequently, more detailed analyses of the t(3;5)(q21;q31) revealed fusion of NR3C1 to a long noncoding RNA (lncRNA) gene (lincRNA-3q) that encodes a novel, nuclear, noncoding RNA involved in the regulation of leukemia stem cell programs and G1/S transition, via E2F. Overexpression of lincRNA-3q was a consistent feature of malignant cells and could be abrogated by bromodomain and extraterminal domain (BET) protein inhibition. Taken together, this work points to NR3C1 as a haploinsufficient tumor suppressor in a subset of BPDCN and identifies BET inhibition, acting at least partially via lncRNA blockade, as a novel treatment option in BPDCN. (Blood. 2016;127(24):3040-3053)

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BET Bromodomain Inhibition Suppresses the Function of Hematopoietic Transcription Factors in Acute Myeloid Leukemia

Cited by 296 publications

References 54 publications

PAX3–FOXO1 Establishes Myogenic Super Enhancers and Confers BET Bromodomain Vulnerability

PAX3–FOXO1 Establishes Myogenic Super Enhancers and Confers BET Bromodomain Vulnerability

BET bromodomain inhibition enhances T cell persistence and function in adoptive immunotherapy models

Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms

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