%0 Journal Article
%T Mutations in Epigenetic Modifiers in Myeloid Malignancies and the Prospect of Novel Epigenetic-Targeted Therapy
%A Amir T. Fathi
%A Omar Abdel-Wahab
%J Advances in Hematology
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/469592
%X In the recent years, the discovery of a series of mutations in patients with myeloid malignancies has provided insight into the pathogenesis of myelodysplastic syndromes (MDSs), myeloproliferative neoplasms (MPNs), and acute myeloid leukemia (AML). Among these alterations have been mutations in genes, such as IDH1/2, TET2, DNMT3A, and EZH2, which appear to affect DNA and/or histone lysine methylation. Large clinical correlative studies are beginning to decipher the clinical importance, prevalence, and potential prognostic significance of these mutations. Additionally, burgeoning insight into the role of epigenetics in the pathogenesis of myeloid malignancies has prompted increased interest in development of novel therapies which target DNA and histone posttranslational modifications. DNA demethylating agents have been demonstrated to be clinically active in a subset of patients with MDS and AML and are used extensively. However, newer, more specific agents which alter DNA and histone modification are under preclinical study and development and are likely to expand our therapeutic options for these diseases in the near future. Here, we review the current understanding of the clinical importance of these newly discovered mutations in AML and MDS patients. We also discuss exciting developments in DNA methyltransferase inhibitor strategies and the prospect of novel histone lysine methyltransferase inhibitors. 1. Introduction The increasing use of systematic genome-wide discovery efforts in patients with a variety of myeloid malignancies has led to the rapid discovery of a series of recurrent genetic abnormalities underlying these disorders. Remarkably, a large number of these alterations appear to be in genes whose function is known, or suspected, to be involved in epigenetic regulation of gene transcription. In the last 3 years, alone mutations in the genes TET2, IDH1, IDH2, DNMT3a, and EZH2 have all been found in patients with myeloproliferative neoplasms (MPNs), myelodysplastic syndromes (MDSs), and/or acute myeloid leukemia (AML). Although the functional implications of these mutations and how precisely they contribute to abnormal hematopoiesis and leukemogenesis is being heavily investigated and not yet clarified, a number of potentially clinically important implications of these mutations may already be apparent. First, mutations in several of these genes likely hold prognostic importance for patients, and these genetic alterations, thereby, may serve as prognostic markers for risk stratification and aid in therapeutic decision making. Secondly,
%U http://www.hindawi.com/journals/ah/2012/469592/