Frequency, onset and clinical impact of somatic DNMT3A mutations in therapy-related and secondary acute myeloid leukemia

Fried, Isabella; Bodner, Claudia; Pichler, Monika M.; Lind, Karin; Beham‐Schmid, Christine; Quehenberger, Franz; Sperr, Wolfgang R.; Linkesch, Werner; Sill, Heinz; Wölfler, Albert

doi:10.3324/haematol.2011.051581

Cited by 48 publications

(35 citation statements)

References 14 publications

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“…Mutations of DNMT3A are reported in 18-23 % of AML, including 20-35 % with normal karyotype, 8 % of MDS and 7-15 % of MPN [34,36,50,[56][57][58]. The locus of the mutations is clustered at R882 in a half of cases and distributed widely in other cases.…”

Section: Dnmt3amentioning

confidence: 99%

“…DNMT3A mutations might be associated with poorer prognosis, and is frequently associated with NPM1 and FLT3 mutations [34,50,[56][57][58]. Several different loss-offunction mutations have been found in all exons of DNMT3A, while a missense point mutation at amino acid R882 which decreases catalytic activity and DNA binding affinity is most frequently identified.…”

Section: Dnmt3amentioning

confidence: 99%

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Gene mutations of acute myeloid leukemia in the genome era

Naoe

Kiyoi

2013

Int J Hematol

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Ten years ago, gene mutations found in acute myeloid leukemia (AML) were conceptually grouped into class I mutation, which causes constitutive activation of intracellular signals that contribute to the growth and survival, and class II mutation, which blocks differentiation and/or enhance self-renewal by altered transcription factors. A cooperative model between two classes of mutations has been suggested by murine experiments and partly supported by epidemiological findings. In the last 5 years, comprehensive genomic analysis proceeded to find new gene mutations, which are found in the epigenome-associated enzymes and the molecules never noticed so far. These new mutations apparently increase the complexity and heterogeneity of AML. Although a long list of gene mutations might have been compiled, the entire picture of molecular pathogenesis in AML remains to be elucidated because gene rearrangement, gene copy number, DNA methylation and expression profiles are not fully studied in conjunction with gene mutations. Comprehensive genome research will deepen the understanding of AML to promote the development of new classification and treatment. This review focuses on gene mutations that were recently discovered by genome sequencing.

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Section: Dnmt3amentioning

confidence: 99%

Section: Dnmt3amentioning

confidence: 99%

Gene mutations of acute myeloid leukemia in the genome era

Naoe

Kiyoi

2013

Int J Hematol

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“…89 Although previous studies clearly pointed to an oncogenic role of DNMT3A in cancer, the recent discovery of genetic mutations of DNMT3A in acute myeloid leukemia (AML) suggested that its role in cancers may be more complex than was previously believed. [11][12][13][14][15][16][17][18][19][20][21][22][23] These highly recurrent DNMT3A mutations were closely associated with poor outcome in patients with AML. However, the functional implications of these mutations are still poorly understood.…”

Section: The Dual Roles Of Dnmt3a In Cancermentioning

confidence: 99%

“…10 However, several inactivating mutations of DNMT3A in myeloid malignancies [11][12][13][14][15][16][17][18][19][20][21][22][23] and loss of DNMT3A activity at advanced tumor stages 24 were recently identified. In addition, novel roles of DNMT3A in the hematopoiesis system 25 and in the age-related decline of cognition 26 have been revealed.…”

Section: Introductionmentioning

confidence: 99%

The de novo DNA methyltransferase DNMT3A in development and cancer

Chen

Chan

2014

Epigenetics

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“…DNMT3A mutations in secondary AML have been described to be present in the corresponding antecedent MDS or MPN, in a series of ten patients, suggestive of an early event (Fried et al, 2012). In addition to the DNMT3A mutation, our patient had an NRAS G13D; NRAS mutations occur in around 10-13% of patients with AML but do not confer any significant prognostic impact (Bacher et al, 2006;Schlenk et al, 2008).…”

Section: Discussionmentioning

confidence: 89%

Genomic profiling and directed ex vivo drug analysis of an unclassifiable myelodysplastic/myeloproliferative neoplasm progressing into acute myeloid leukemia

Hyrenius-Wittsten

Sturesson

Bidgoli

et al. 2016

Genes Chromosomes & Cancer

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Myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN‐U) are rare genetically heterogeneous hematologic diseases associated with older age and a poor prognosis. If the disease progresses into acute myeloid leukemia (AML), it is often refractory to treatment. To gain insight into genetic alterations associated with disease progression, whole exome sequencing and single nucleotide polymorphism arrays were used to characterize the bone marrow and blood samples from a 39‐year‐old woman at MDS/MPN‐U diagnosis and at AML progression, in which routine genetic diagnostics had not identified any genetic alterations. The data revealed the presence of a partial tandem duplication of the MLL gene as the only detectable copy number change and 11 non‐silent somatic mutations, including DNMT3A R882H and NRAS G13D. All somatic lesions were present both at initial MDS/MPN‐U diagnosis and at AML presentation at similar mutant allele frequencies. The patient has since had two extramedullary relapses and is at high risk of a future bone marrow relapse. A directed ex vivo drug sensitivity analysis showed that the patient's AML cells are sensitive to, for example, the MEK inhibitor trametinib and the proteasome inhibitor bortezomib, indicating that she may benefit from treatment with these drugs. © 2016 Wiley Periodicals, Inc.

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Frequency, onset and clinical impact of somatic DNMT3A mutations in therapy-related and secondary acute myeloid leukemia

Cited by 48 publications

References 14 publications

Gene mutations of acute myeloid leukemia in the genome era

Gene mutations of acute myeloid leukemia in the genome era

The de novo DNA methyltransferase DNMT3A in development and cancer

Genomic profiling and directed ex vivo drug analysis of an unclassifiable myelodysplastic/myeloproliferative neoplasm progressing into acute myeloid leukemia

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