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.