title: EZH2 mutational status predicts poor survival in myelofibrosis.
abstract: We genotyped 370 subjects with primary myelofibrosis (PMF) and 148 with postpolycythemia vera/postessential thrombocythemia (PPV/PET) MF for mutations of EZH2. Mutational status at diagnosis was correlated with hematologic parameters, clinical manifestations, and outcome. A total of 25 different EZH2 mutations were detected in 5.9% of PMF, 1.2% of PPV-MF, and 9.4% of PET-MF patients; most were exonic heterozygous missense changes. EZH2 mutation coexisted with JAK2V617F or ASXL1 mutation in 12 of 29 (41.4%) and 6 of 27 (22.2%) evaluated patients; TET2 and CBL mutations were found in 2 and 1 patients, respectively. EZH2-mutated PMF patients had significantly higher leukocyte counts, blast-cell counts, and larger spleens at diagnosis, and most of them (52.6%) were in the high-risk International Prognostic Score System (IPSS) category. After a median follow-up of 39 months, 128 patients (25.9%) died, 81 (63.3%) because of leukemia. Leukemia-free survival (LFS) and overall survival (OS) were significantly reduced in EZH2-mutated PMF patients (P = .028 and P < .001, respectively); no such impact was seen for PPV/PET-MF patients, possibly due to the low number of mutated cases. In multivariate analysis, survival of PMF patients was predicted by IPSS high-risk category, a < 25% JAK2V617F allele burden, and EZH2 mutation status. We conclude that EZH2 mutations are independently associated with shorter survival in patients with PMF.
authors.affiliation: Department of Medical and Surgical Critical Care, Section of Hematology, University of Florence, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Guglielmelli
authors.forename: Flavia
authors.initials: F
authors.lastname: Biamonte
authors.forename: Joannah
authors.initials: J
authors.lastname: Score
authors.forename: Claire
authors.initials: C
authors.lastname: Hidalgo-Curtis
authors.forename: Francisco
authors.initials: F
authors.lastname: Cervantes
authors.forename: Margherita
authors.initials: M
authors.lastname: Maffioli
authors.forename: Tiziana
authors.initials: T
authors.lastname: Fanelli
authors.forename: Thomas
authors.initials: T
authors.lastname: Ernst
authors.forename: Nils
authors.initials: N
authors.lastname: Winkelman
authors.forename: Amy V
authors.initials: AV
authors.lastname: Jones
authors.forename: Katerina
authors.initials: K
authors.lastname: Zoi
authors.forename: Andreas
authors.initials: A
authors.lastname: Reiter
authors.forename: Andrew
authors.initials: A
authors.lastname: Duncombe
authors.forename: Laura
authors.initials: L
authors.lastname: Villani
authors.forename: Alberto
authors.initials: A
authors.lastname: Bosi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Barosi
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Vannucchi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004268:DNA-Binding Proteins / Q000235:genetics*; D018572:Disease-Free Survival; D000071221:Enhancer of Zeste Homolog 2 Protein; D005091:Exons; D005260:Female; D006579:Heterozygote; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D063151:Polycomb Repressive Complex 2; D011087:Polycythemia Vera / Q000209:etiology / Q000235:genetics; D055728:Primary Myelofibrosis / Q000150:complications / Q000235:genetics*; D011379:Prognosis; D012097:Repressor Proteins / Q000235:genetics; D013920:Thrombocythemia, Essential / Q000209:etiology / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult
chemical_list: C473949:ASXL1 protein, human; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C507924:JAK2 protein, human; D053614:Janus Kinase 2