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. (Blood. 2011;118(19):5227-5234) IntroductionThe identification of the JAK2V617F mutation 1-4 represented a seminal discovery in the field of Philadelphia-chromosomenegative chronic myeloproliferative neoplasms (MPNs), 5 providing clues to the pathogenesis, 6 prompting a revision of the diagnostic criteria, 7 and culminating in the development of clinical trials with JAK2 (and JAK1) inhibitors. 8,9 The JAK2V617F mutation occurs in almost all patients with polycythemia vera (PV) and in 50%-70% of those with essential thrombocythemia (ET) and primary myelofibrosis (PMF). Soon after the identification of the JAK2V617F mutation, mutations in JAK2 exon 12 were described in rare patients with JAK2V617F-negative PV and mutations in MPL were reported in 5%-10% of ET or PMF subjects. The complexity of the molecular pathogenesis of MPNs is reinforced by discovery of additional mutations in TET2, 10 ASXL1, 11 CBL, 12 IDH1/IDH2, 13 and IKZF1. 14 These mutations are detected in a minority of patients at different phases of the disorder, including leukemic transformation, and are variably associated each other and with JAK2 or MPL mutations.We recently identified novel loss-of-function mutations in EZH2 in 1 of 30 (3%) PV and in 4 of 30 PMF patients (13%), as well as in 11%-25% of patients with myelodysplastic syndromes (MDS) and in 10% of patients with MDS/MPN. 15 Mutations were spread throughout the gene and included missense, nonsense, and premature stop codons; both monoallelic and biallelic mutations were described. Among patients with MDS/MPN, survival was significantly worse in those with EZH2 muta...

One Thousand Patients With Primary Myelofibrosis: The Mayo Clinic Experience

“…39,40 We have in the past consistently shown the independent prognostic value of cytogenetic abnormalities, 31,[41][42][43][44] as well as thrombocytopenia 45,46 and red blood cell transfusion need, 47 in PMF. Similarly, there is no doubt that the current prognostic models will be further refined on the basis of new information regarding DIPSS-plus-independent genetic 48,49 and biological 50 risk factors, some of which also appear to be relevant in the context of myelodysplastic syndromes. [51][52][53] On the basis of observations from the current study, we recommend the use of DIPSS-plus 21 as the principal prognostic tool in PMF, both at time of diagnosis and at any point during the disease course.…”

Polycomb repressive complex 2 is required for MLL-AF9 leukemia

“…In the hematopoietic system, forced expression of Ezh2 increases serial transplantation potential in hematopoietic stem cells (6) and enhances transformation in a model of multiple myeloma (7). Intriguingly, heterozygous loss of function of EZH2 has been associated with adverse prognosis in myelofibrosis (8), and heterozygous and homozygous inactivation of EZH2 has been described in myelodysplastic syndromes and more recently in Tlineage lymphoblastic leukemia (9)(10)(11)(12). In contrast, EZH2 alterations appear to be rare events in acute myeloid leukemia (AML).…”

Absence of EZH2 Gene Mutation in Chronic Myeloid Leukemia Patients in Blast Crisis

“…In addition, EZH2 mutations were independently associated with shorter survival in patients with primary myelofibrosis (PMF) (Guglielmelli et al, 2011). These results indicate that EZH2 plays an important role in hematological disease.…”

“…Mutations in the EZH2 gene were recently described in patients with B-cell lymphomas (Morin et al, 2010), chronic myelomonocytic leukemia (CMML) ( Jankowska et al, 2011), adult and pediatric acute myeloid leukemia (Makishima et al, 2010;Ernst et al, 2012), myelofibrosis (Guglielmelli et al, 2011), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and the overlap myelodysplastic/myeloproliferative neoplasms (MDS/MPN) (Ernst et al, 2010;Makishima et al, 2010). It was revealed that EZH2 mutations were correlated with poor survival.…”