EZH2 mutational status predicts poor survival in myelofibrosis

• Published in: Blood Vol. 118; no. 19; pp. 5227 - 5234
• Main Authors: Guglielmelli, Paola, Biamonte, Flavia, Score, Joannah, Hidalgo-Curtis, Claire, Cervantes, Francisco, Maffioli, Margherita, Fanelli, Tiziana, Ernst, Thomas, Winkelman, Nils, Jones, Amy V., Zoi, Katerina, Reiter, Andreas, Duncombe, Andrew, Villani, Laura, Bosi, Alberto, Barosi, Giovanni, Cross, Nicholas C.P., Vannucchi, Alessandro M.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 10.11.2011; Americain Society of Hematology
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Biological and medical sciences; Disease-Free Survival; DNA-Binding Proteins - genetics; Enhancer of Zeste Homolog 2 Protein; Exons; Female; Hematologic and hematopoietic diseases; Heterozygote; Humans; Janus Kinase 2 - genetics; Kaplan-Meier Estimate; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Middle Aged; Mutation; Mutation, Missense; Polycomb Repressive Complex 2; Polycythemia Vera - etiology; Polycythemia Vera - genetics; Primary Myelofibrosis - complications; Primary Myelofibrosis - genetics; Prognosis; Repressor Proteins - genetics; Thrombocythemia, Essential - etiology; Thrombocythemia, Essential - genetics; Transcription Factors - genetics; Young Adult; Histone-lysine N-methyltransferase; Myelofibrosis; Hematology; Enzyme; Transferases; Transcription repressor; Hemopathy; Survival; Myeloproliferative syndrome; Methyltransferases; Ezh2 gene; Genetics; Mutation; Predictive factor
• DOI: 10.1182/blood-2011-06-363424
• ISSN: 0006-4971; 1528-0020

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.