title: A687V EZH2 is a gain-of-function mutation found in lymphoma patients.
abstract: Heterozygous point mutations at Y641 and A677 in the EZH2 SET domain are prevalent in about 10-24% of Non-Hodgkin lymphomas (NHL). Previous studies indicate that these are gain-of-function mutations leading to the hypertrimethylation of H3K27. These EZH2 mutations may drive the proliferation of lymphoma and make EZH2 a molecular target for patients harboring these mutations. Here, another EZH2 SET domain point mutation, A687V, occurring in about 1-2% of lymphoma patients, is also shown to be a gain-of-function mutation that greatly enhances its ability to perform dimethylation relative to wild-type EZH2 and is equally proficient at catalyzing trimethylation. We propose that A687V EZH2 also leads to hypertrimethylation of H3K27 and may thus be a driver mutation in NHL.
authors: Epizyme, Inc., 325 Vassar St., Cambridge, MA 02139, USA.
authors: Christina R
authors: CR
authors: Majer
authors: Lei
authors: L
authors: Jin
authors: Margaret Porter
authors: MP
authors: Scott
authors: Sarah K
authors: SK
authors: Knutson
authors: Kevin W
authors: KW
authors: Kuntz
authors: Heike
authors: H
authors: Keilhack
authors: Jesse J
authors: JJ
authors: Smith
authors: Mikel P
authors: MP
authors: Moyer
authors: Victoria M
authors: VM
authors: Richon
authors: Robert A
authors: RA
authors: Copeland
authors: Tim J
authors: TJ
authors: Wigle
mesh_terms: D000071221:Enhancer of Zeste Homolog 2 Protein; D006579:Heterozygote; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008228:Lymphoma, Non-Hodgkin / Q000201:enzymology* / Q000235:genetics*; D008745:Methylation; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D063151:Polycomb Repressive Complex 2 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D006657:Histones; D050505:Mutant Proteins; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2