DNMT3A mutations in myeloproliferative neoplasms

Stegelmann, Frank; Bullinger, Lars; Schlenk, Richard F.; Paschka, Peter; Grießhammer, Martin; Blersch, Carmen; Kuhn, Susanne; Schauer, Stefanie; Döhner, Hartmut; Döhner, Konstanze

doi:10.1038/leu.2011.77

Cited by 154 publications

(116 citation statements)

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“…Considering their high occurrence and prognostic significance, it is likely that DNMT3A mutations belong to this category in CN-AML. Of note, DNMT3A mutations have also been reported in other myeloid malignancies, such as myeloproliferative neoplasms 52 and myelodysplastic syndromes, 53 but with a much lower incidence. In myelodysplastic syndromes, DNMT3A mutations also seem to predict poor prognosis with shorter survival and more rapid progression to AML.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association

et al. 2012

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Recently, DNA methyltransferase 3A (DNMT3A) mutations have been identified in acute myeloid leukemia (AML), the highest frequency being found within cytogenetically normal (CN) AML. In this study, diagnostic samples from 123 adults younger than 60 years with primary CN-AML homogeneously treated in the Acute Leukemia French Association-9801 and -9802 trials were screened for mutations in DNMT3A-conserved domains by direct sequencing. Patients were also assessed for the presence of FLT3 (fms-like tyrosine kinase receptor-3), NPM1 (nucleophosmin), CEBPA, WT1 (Wilms tumor 1), IDH1 (isocitrate dehydrogenase 1) and IDH2 mutations. Thirty-eight mutations were detected in 36 patients (29%): 36 nucleotide substitutions, mostly affecting amino-acid residue R882 and two frameshift deletions. DNMT3A mutations were significantly associated with the French --American --British subtypes M4/M5 and the presence of NPM1 mutations. In the whole cohort, DNMT3A mutated patients had a shorter event-free survival (5-year EFS: 13% vs 32%, P ¼ 0.02) and overall survival (5-year OS: 23% vs 45%, P ¼ 0.02) compared with DNMT3A wild-type patients. In multivariate analysis including age, white blood cell count, NPM1/FLT3-internal tandem duplication/CEBPA risk group and DNMT3A mutational status, the presence of a DNMT3A mutation remained an independent adverse prognostic factor for EFS and OS, suggesting that testing for DNMT3A mutations could help further improve risk stratification in CN-AML.

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Section: Discussionmentioning

confidence: 99%

Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association

et al. 2012

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“…33 Most recently, DNA methyltransferase 3a (DNMT3A) mutations were reported in patients with acute myeloid leukemia, MDS, and MPN; mutational frequencies in the latter were reported at ϳ7% for PV, 6% for PMF, and 14% for blast-phase MPN. 35 Another study of 46 patients with PMF, 22 with post-ET/PV myelofibrosis, and 11 with blastphase MPN reported corresponding DNMT3A mutational frequencies of 7%, 0%, and 0%, respectively. 36 All 13 DNMT3A mutations reported in those two studies were heterozygous, and the most frequent mutations affected amino acid R882.…”

Section: Jak2 and Mpl Mutation Tests In Mpns 463mentioning

confidence: 99%

Uses and Abuses of JAK2 and MPL Mutation Tests in Myeloproliferative Neoplasms

Tefferi

Noël

Hanson

2011

The Journal of Molecular Diagnostics

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JAK2V617F is sufficiently prevalent in BCR-ABL1-negative myeloproliferative neoplasms (MPNs) to be useful as a clonal marker. JAK2V617F mutation screening is indicated for the evaluation of erythrocytosis, thrombocytosis, splanchnic vein thrombosis, and otherwise unexplained BCR-ABL1-negative granulocytosis. However, the mutation does not provide additional value in the presence of unequivocal morphologic diagnosis, and its presence does not necessarily distinguish one MPN from another or provide useful prognostic information. In general, quantitative cell-based JAK2V617F mutation assays are preferred because the additional information obtained on mutant allele burden enhances diagnostic certainty and facilitates monitoring of response to treatment. JAK2 exon 12 mutation screening is indicated only in the presence of JAK2V617F-negative erythrocytosis that is associated with a subnormal serum erythropoietin level. MPL mutations are neither frequent nor specific enough to warrant their routine use for MPN diagnosis, but they may be useful in resolving specific diagnostic problems. The practice of en bloc screening for JAK2V617F, JAK2 exon 12, and MPL mutations is scientifically irrational and economically irresponsible. Morphology is the cornerstone of current diagnosis and classification in myeloid malignancies. 1 Cytochemical, immunophenotypic, cytogenetic, and molecular data enhance diagnostic accuracy and form the basis for the World Health Organization classification of myeloid malignancies into five main categories 2 : acute myeloid leukemia, myelodysplastic syndromes (MDSs), myeloproliferative neoplasms (MPNs), MDS/MPN overlap, and platelet-derived growth factor receptor gene or fibroblast growth factor receptor 1 gene rearranged myeloid/lymphoid neoplasms associated with eosinophilia. The World Health Organization MPN category includes eight subcategories: chronic myelogenous leukemia, polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), mastocytosis, chronic eosinophilic leukemia not otherwise specified, chronic neutrophilic leukemia, and MPN unclassifiable. 1 Among these subcategories, the first four (ie, chronic myelogenous leukemia, PV, ET, and PMF) are currently referred to as "classic" MPNs, because they were included in the original description of myeloproliferative disorders by William Dameshek. 3 In general, current evidence supports consideration of all myeloid malignancies, including MPN, as clonal stem cell diseases.JAK2 and MPL mutations occur across the spectrum of myeloid malignancies, including MPN, MDS, MDS/MPN, and acute myeloid leukemia (Table 1). 4 -7 These mutations are most prevalent in the BCR-ABL1-negative classic MPN (ie, PV, ET, and PMF), which are morphologically characterized by the absence of both cellular dysplasia

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“…69 Loss-of-function mutations (including dominant negative missense mutations at codon 882) in DNA methyltransferase 3A (DNMT3A), a protein responsible for de novo methylation of CpG dinucleotides, are found across MPN subtypes. 73 As with TET2 mutations, their exact role in MPN pathogenesis is not yet fully understood, but it is thought that the resultant epigenetic deregulation results in the upregulation of "HSC fingerprint" genes such as GATA3 and RUNX1 and the downregulation of differentiation factors such as Ikaros, together resulting in a differentiation block and HSC expansion. 74 Mutations of genes involved in histone methylation are overrepresented in myelofibrosis/transformed disease.…”

Section: Mutations In Epigenetic Regulatorsmentioning

confidence: 99%