title: Inactivation of polycomb repressive complex 2 components in myeloproliferative and myelodysplastic/myeloproliferative neoplasms.
abstract: The polycomb repressive complex 2 (PRC2) is a highly conserved histone H3 lysine 27 methyltransferase that regulates the expression of developmental genes. Inactivating mutations of the catalytic component of PRC2, EZH2, are seen in myeloid disorders. We reasoned that the other 2 core PRC2 components, SUZ12 and EED, may also be mutational targets in these diseases, as well as associated factors such as JARID2. SUZ12 mutations were identified in 1 of 2 patients with myelodysplastic syndrome/myeloproliferative neoplasms with 17q acquired uniparental disomy and in 2 of 2 myelofibrosis cases with focal 17q11 deletions. All 3 were missense mutations affecting the highly conserved VEFS domain. Analysis of a further 146 myelodysplastic syndrome/myeloproliferative neoplasm patients revealed an additional VEFS domain mutant, yielding a total mutation frequency of 1.4% (2 of 148). We did not find mutations of JARID2 or EED in association with acquired uniparental disomy for chromosome 6p or 11q, respectively; however, screening unselected cases identified missense mutations in EED (1 of 148; 1%) and JARID2 (3 of 148; 2%). All 3 SUZ12 mutations tested and the EED mutation reduced PRC2 histone methyltransferase activity in vitro, demonstrating that PRC2 function may be compromised in myeloid disorders by mutation of distinct genes.
authors: Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors: Joannah
authors: J
authors: Score
authors: Claire
authors: C
authors: Hidalgo-Curtis
authors: Amy V
authors: AV
authors: Jones
authors: Nils
authors: N
authors: Winkelmann
authors: Alison
authors: A
authors: Skinner
authors: Daniel
authors: D
authors: Ward
authors: Katerina
authors: K
authors: Zoi
authors: Thomas
authors: T
authors: Ernst
authors: Frank
authors: F
authors: Stegelmann
authors: Konstanze
authors: K
authors: Döhner
authors: Andrew
authors: A
authors: Chase
authors: Nicholas C P
authors: NC
authors: Cross
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D019046:Bone Marrow Neoplasms / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D054437:Myelodysplastic-Myeloproliferative Diseases / Q000235:genetics*; D009196:Myeloproliferative Disorders / Q000235:genetics*; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
chemical_list: D063146:Polycomb-Group Proteins; D012097:Repressor Proteins