A687V EZH2 is a gain-of-function mutation found in lymphoma patients |
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Authors: | Christina R. MajerLei Jin Margaret Porter ScottSarah K. Knutson Kevin W. KuntzHeike Keilhack Jesse J. SmithMikel P. Moyer Victoria M. RichonRobert A. Copeland Tim J. Wigle |
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Affiliation: | Epizyme, Inc., 325 Vassar St., Cambridge, MA 02139, USA |
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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. |
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Keywords: | DLBCL, diffuse large B-cell lymphoma CPM, counts per minute GCB, germinal Center B-cell-like H3K27, histone H3 lysine 27 NHL, non-Hogdkin lymphoma PKMT, protein lysine methyltransferase PRC2, Polycomb Repressive Complex 2 SAM, S-adenosylmethionine SAH, S-adenosylhomocysteine 3H-SAM, SAM bearing tritiated methyl group |
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