Clinical Implications of Novel Mutations in Epigenetic Modifiers in AML

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Epigenetic modifiers mutated in AML

Conventional and molecular cytogenetics are essential components of risk stratification and therapeutic decision making in the clinical management of patients with acute myeloid leukemia (AML). In addition to structural chromosomal alterations, molecular analysis of mutations have been incorporated into the World Health Organization (WHO) and European Leukemia Net (ELN) AML classification; specifically, mutations in FLT3, NPM1, and CEBPA are now broadly accepted in routine clinical practice.1

Mutations and deletions in TET2: a potentially important prognosticator in CN-AML

TET2 is member of the Tet family of enzymes, Fe(Ii)-, α-ketoglutarate–dependent enzymes with a previously unknown function, specially the ability to convert 5-methylcytosine to 5-hydroxymethylcytosine,6 an enzymatic activity that is now believed to be critical in mediating DNA demethylation.7 Somatic mutations in TET2 were first identified in 2009 and occur throughout the coding region of TET2 as deletion mutations, missense, nonsense, and frameshift mutations in patients with

Gain-of-function mutations in IDH1 and IDH2 in AML

Somatic mutations in human cytosolic isocitrate dehydrogenase 1 (IDH1) and mitochondrial isocitrate dehydrogenase 2 (IDH2) are now well-recognized recurrent genetic alterations in AML.24 The mutations in IDH1 occur at R132 and were initially reported to cause loss of the enzyme’s normal ability to catalyze the conversion of isocitrate to α-ketoglutarate. Subsequently, investigators discovered that these mutations also conferred a neomorphic gain-of-function: the novel nicotinamide adenine

Mutations in DNMT3a in AML

From June 2010 to April 2011, three groups independently reported mutations in the DNA methyltransferase 3A gene (DNMT3a) in patients with AML (Table 3).35, 36, 37 Since that time, DNMT3a mutations have been further described in additional AML cohorts and in patients with MDS38 and MPN.39 Somatic mutations in the other DNMTs (DNMT1, DNMT3A, DNMT3L) have not been described in AML or other malignancies.

The aggregate of data from the clinical studies performed thus far suggest that DNMT3a

Novel epigenetic gene mutations in pediatric AML

Compared with studies among adults with AML, fewer studies of the frequencies and effects of mutations in TET2, IDH1/2, and DNMT3a have been performed in pediatric patients with AML (Table 4). These studies, however, show that mutations in all of these genes are rare among pediatric patients with AML, occurring in fewer than 5%.41, 42, 43, 44 These findings highlight potentially important biologic differences between pediatric and adult AML regarding the role of somatic alterations in

Potential use of TET2, IDH1/2, and DNMT3a alterations for minimal residual disease detection

Increased identification of cytogenetic and molecular abnormalities in patients with AML has led to an interest in identifying the presence of these genetic alterations in patient samples at diagnosis, remission, and relapse. These studies inform about not only the biologic contributions of these mutations to myelopoiesis but also their potential use in minimal residual disease detection (not yet a well-studied or standardized practice in AML management). It has recently been shown that FLT3-ITD

Summary

The studies highlighted in this article suggest that mutations in TET2 mutations may impart adverse outcome in patients with CN-AML, whereas mutations in DNMT3a may have adverse implications in a broader set of patients with AML. The data with IDH enzyme mutations are less clear, in that individual IDH1 and IDH2 mutations may have different clinical effects and the data so far have not suggested a uniform effect on outcome.

Despite the exciting data indicating that mutational testing for these

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    This work was supported in part by grants from the National Institutes of Health (U54CA143798-01, Physical Sciences Oncology Center) and the Starr Cancer Consortium and Howard Hughes Medical Institute to Dr Levine. Dr Abdel-Wahab is a Basic Research Fellow of the American Society of Hematology.

    The authors have nothing to disclose.

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