Our understanding of the genetic basis of myeloid malignanci

Our understanding of the genetic basis of myeloid malignancies has been profoundly improved in recent years. Studies have revealed new recurrent somatic mutations in myeloid malignancies, including myeloproliferative neoplasms (MPNs), myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Mutations in several tumor suppressors and oncogenes were identified in patients with MDS. Epigenetic regulatory genes involved in modifications of histones (EZH2 and ASXL1) have been identified to bear mutations in people with MDS [19]. Conversely, a genetic study investigating mutations in genes involved in epigenetic modifications in 153 patients of Chinese descent with MDS reported that mutations in TET2 (involved in DNA modification) and ASXL1 (a histone modifier) were common whereas EZH2 mutations were rare [20]. However, previously, inactivating mutations of EZH2 have been identified in myelodysplastic syndromes supporting the notion that EZH2 functions as a tumor suppressor in certain cellular contexts [21,22]. Wang et al. found that EZH2 mutations were associated with poor leukemia-free survival but were not an independent predictor of survival in multivariate analyses [20]. In several other studies the clinical effects of EZH2 mutations have also been reported to be associated with decreased survival of patients with myeloid malignancies [21,[23], [24], [25]]. Myelodysplastic syndromes represent many common features with acute myeloid leukemias [26]. At the molecular genetics level, chromosome 7 loss (-7) or ati stock quote on 7q (7q-) is common in both AML and myelodysplastic syndromes and it is an adverse prognostic factor [27]. EZH2, located at Cr.7q36.1 has been recognized as associated gene on chromosome 7 in MDS [22] although AML patients with del7 or 7q deletions were initially found with no mutation in EZH2 [21]. Whereas a recent study has found EZH2 to be downregulated in individuals with chemoresistant AML with -7/7q- who are associated with poor prognosis [28], on the other hand it was reported that loss of EZH2 prevents transformation to AML in EZH2 mutant MDS mouse models [29]. Given that ectopic expression of Hoxa9 has potential to induce transformation to AML, resistance to transformation in EZH2-null MDS cells is believed to be partly related to repression of Hoxa9 and MECOM/EVI1 expression [2930]. Concerning the associated molecular events, it is clear that EZH2 absence can lead to activation of its target genes while EZH2 target genes in EZH2_null MDS cells are at transcriptionally active state, suggesting that the complementary function of Ezh1 may account for this gene repression [29]. In contrast to the studies correlating EZH2 loss with MDS, it has also been shown that EZH2 overexpression leads to myeloproliferative neoplasms [31]. Similarly, Xu et al. reported that patients with MDS commonly show overexpression of EZH2, which is linked with unfavorable prognosis and pathogenesis of myelodysplastic syndromes [32]. Nevertheless, most studies suggest that EZH2 loss rather than overexpression is more associated with MDS. EZH2 mutations in myeloid neoplasms, have been described in 10–13% of poor-prognosis myelodysplasia-myeloproliferative neoplasms (MDS/MPN), 13% of myelofibrosis (MF), and 6% of MDS [22]. However, the prevalence and prognostic value of EZH2 mutations in individuals with AML is still uncertain. Apart from MDS-derived AML, it is reported that the frequency of EZH2 mutations was 1.8% in an analysis of 714 patients with de novo AML [33] which implies that loss of function mutations of EZH2 are rare in de novo AML. Among patients analyzed in this study, nonsense, frame shift, and missense mutations were detected in 7.1%, 28.6% and 64.3% of all of EZH2 mutations, respectively, displaying a heterozygous pattern [33]. To our knowledge, although mutations of EZH2 appears to be a rare event, there is a clinical evidence describing that specific cases of childhood AML might harbor EZH2 mutations [34]. So larger studies are required to assess EZH2 mutations in childhood AML patients particularly in children carrying t(8;21) translocation [34]. Overall, it is not yet fully clear whether EZH2 is affected and contributes to the disease in MDS and AML patients.