Genetic defects in PRC2 components other than EZH2 are not common in myeloid malignancies

Kroeze, Leonie I.; Nikoloski, Gorica; Silva-Coelho, Pedro da; Hoogen, Patricia van den; Stevens-Linders, Ellen; Kuiper, Roland P.; Schnittger, Susanne; Haferlach, Torsten; Pahl, Heike L.; Reijden, Bert A. van der; Jansen, Joop H.

doi:10.1182/blood-2011-07-365213

Cited by 14 publications

(8 citation statements)

References 7 publications

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“…EZH2 is the most frequently mutated PcG member in the pathogenesis of hematological malignancies (Kroeze et al 2012;Woods and Levine 2015). EZH2 overexpression is commonly observed in various epithelial malignancies, including breast and prostate cancer, suggesting that EZH2 functions as an oncogene (Varambally et al 2002;Kleer et al 2003;Li et al 2009a).…”

Section: Polycomb Group (Pcg) Proteins In Normal and Malignant Hematomentioning

confidence: 99%

Epigenetics of hematopoiesis and hematological malignancies

Hu¹,

Shilatifard

2016

Genes Dev.

139

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Hematological malignancies comprise a diverse set of lymphoid and myeloid neoplasms in which normal hematopoiesis has gone awry and together account for ∼10% of all new cancer cases diagnosed in the United States in 2016. Recent intensive genomic sequencing of hematopoietic malignancies has identified recurrent mutations in genes that encode regulators of chromatin structure and function, highlighting the central role that aberrant epigenetic regulation plays in the pathogenesis of these neoplasms. Deciphering the molecular mechanisms for how alterations in epigenetic modifiers, specifically histone and DNA methylases and demethylases, drive hematopoietic cancer could provide new avenues for developing novel targeted epigenetic therapies for treating hematological malignancies. Just as past studies of blood cancers led to pioneering discoveries relevant to other cancers, determining the contribution of epigenetic modifiers in hematologic cancers could also have a broader impact on our understanding of the pathogenesis of solid tumors in which these factors are mutated.

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Section: Polycomb Group (Pcg) Proteins In Normal and Malignant Hematomentioning

confidence: 99%

Epigenetics of hematopoiesis and hematological malignancies

Hu¹,

Shilatifard

2016

Genes Dev.

139

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“…Abnormal activation of PRC2 due to genetic mutations in its catalytic subunit EZH2 has been widely studied in lymphoma malignancy [1–7], which serves as the basis for targeting PRC2 as novel therapeutic approach in treating malignant cancers such as follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). We and others have discovered potent PRC2 inhibitors derived from a common pyridone scaffold which compete with the cofactor SAM for EZH2 binding [8–12].…”

Section: Introductionmentioning

confidence: 99%

Discovery and Molecular Basis of a Diverse Set of Polycomb Repressive Complex 2 Inhibitors Recognition by EED

Zhang

et al. 2017

PLoS ONE

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Polycomb repressive complex 2 (PRC2), a histone H3 lysine 27 methyltransferase, plays a key role in gene regulation and is a known epigenetics drug target for cancer therapy. The WD40 domain-containing protein EED is the regulatory subunit of PRC2. It binds to the tri-methylated lysine 27 of the histone H3 (H3K27me3), and through which stimulates the activity of PRC2 allosterically. Recently, we disclosed a novel PRC2 inhibitor EED226 which binds to the K27me3-pocket on EED and showed strong antitumor activity in xenograft mice model. Here, we further report the identification and validation of four other EED binders along with EED162, the parental compound of EED226. The crystal structures for all these five compounds in complex with EED revealed a common deep pocket induced by the binding of this diverse set of compounds. This pocket was created after significant conformational rearrangement of the aromatic cage residues (Y365, Y148 and F97) in the H3K27me3 binding pocket of EED, the width of which was delineated by the side chains of these rearranged residues. In addition, all five compounds interact with the Arg367 at the bottom of the pocket. Each compound also displays unique features in its interaction with EED, suggesting the dynamics of the H3K27me3 pocket in accommodating the binding of different compounds. Our results provide structural insights for rational design of novel EED binder for the inhibition of PRC2 complex activity.

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“…Inactivating mutations of other core PRC2 components in myeloid malignancies are less common suggesting that EZH2 plays an important non-redundant role in hematopoiesis. 159,160 Nonetheless, the dichotomous role played by EZH2 as both an oncogene and tumor suppressor in the development of malignancies highlights the tissuespecific role of H3K27 methylation. Recent data have also linked inactivating ASXL1 mutations to loss of PRC2-mediated H3K27 methylation.…”

Section: The Role Of the Polycomb Group Proteins In Hematological Malmentioning

confidence: 99%

Epigenetics in the hematologic malignancies

2014

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A wealth of genomic and epigenomic data has identified abnormal regulation of epigenetic processes as a prominent theme in hematologic malignancies. Recurrent somatic alterations in myeloid malignancies of key proteins involved in DNA methylation, post-translational histone modification and chromatin remodeling have highlighted the importance of epigenetic regulation of gene expression in the initiation and maintenance of various malignancies. The rational use of targeted epigenetic therapies requires a thorough understanding of the underlying mechanisms of malignant transformation driven by aberrant epigenetic regulators. In this review we provide an overview of the major protagonists in epigenetic regulation, their aberrant role in myeloid malignancies, prognostic significance and potential for therapeutic targeting. ABSTRACT nance,24 DNMT3A and DMNT3B function primarily in de novo methylation during embryogenesis.25 Initial investigations demonstrated abnormalities in the expression of DNMTs in a range of solid organ malignancies. 26,27

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Genetic defects in PRC2 components other than EZH2 are not common in myeloid malignancies

Cited by 14 publications

References 7 publications

Epigenetics of hematopoiesis and hematological malignancies

Epigenetics of hematopoiesis and hematological malignancies

Discovery and Molecular Basis of a Diverse Set of Polycomb Repressive Complex 2 Inhibitors Recognition by EED

Epigenetics in the hematologic malignancies

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