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Title:
Recurrent DNMT3A mutations in patients with myelodysplastic syndromes | Leukemia
Description:
Alterations in DNA methylation have been implicated in the pathogenesis of myelodysplastic syndromes (MDS), although the underlying mechanism remains largely unknown. Methylation of CpG dinucleotides is mediated by DNA methyltransferases, including DNMT1, DNMT3A and DNMT3B. DNMT3A mutations have recently been reported in patients with de novo acute myeloid leukemia (AML), providing a rationale for examining the status of DNMT3A in MDS samples. In this study, we report the frequency of DNMT3A mutations in patients with de novo MDS, and their association with secondary AML. We sequenced all coding exons of DNMT3A using DNA from bone marrow and paired normal cells from 150 patients with MDS and identified 13 heterozygous mutations with predicted translational consequences in 12/150 patients (8.0%). Amino acid R882, located in the methyltransferase domain of DNMT3A, was the most common mutation site, accounting for 4/13 mutations. DNMT3A mutations were expressed in the majority of cells in all tested mutant samples regardless of myeloblast counts, suggesting that DNMT3A mutations occur early in the course of MDS. Patients with DNMT3A mutations had worse overall survival compared with patients without DNMT3A mutations (P=0.005) and more rapid progression to AML (P=0.007), suggesting that DNMT3A mutation status may have prognostic value in de novo MDS.
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nature portfolio permissions reprints privacy policy mo performed research cancer research advertising nature 1999 nature 2004 nature 2010 nature social media array-based genomic resequencing polycomb-group gene enhancer mammalian development springerlink instant access tg analyzed data idh-mutant astrocytoma progression permissions development 1998 de novo methylation author correspondence dnmt3a mutation status personal data amino acid r882 aberrant dna methylation dna methyltransferase gene recurrent dnmt3a mutations immunodeficiency syndrome caused privacy murine dnmt3a dna dna methyltransferases dnmt3a data protection issue learn generated data acute myeloid leukemia common mutation site supplementary figure 1b dnmt3a-destabilizing variants randomized controlled trial de novo mds explore content subscription content germline atrx mutations european economic area predicted translational consequences local taxes institutional subscriptions read barry-holson kq hidalgo-curtis ce severe hematologic phenotype
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- Common 4q24 deletion in four cases of hematopoietic malignancy: early stem cell involvement?
- Myelodysplastic syndromes: lost between two states?
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affiliation:
name:Washington University
address:
name:Department of Internal Medicine, Division of Oncology, Washington University, St Louis, USA
type:PostalAddress
type:Organization
name:Siteman Cancer Center, Washington University
address:
name:Siteman Cancer Center, Washington University, St Louis, USA
type:PostalAddress
type:Organization
name:E R Mardis
affiliation:
name:Washington University
address:
name:Department of Genetics, Washington University, St Louis, USA
type:PostalAddress
type:Organization
name:Siteman Cancer Center, Washington University
address:
name:Siteman Cancer Center, Washington University, St Louis, USA
type:PostalAddress
type:Organization
name:The Genome Institute, Washington University
address:
name:The Genome Institute, Washington University, St Louis, USA
type:PostalAddress
type:Organization
name:R K Wilson
affiliation:
name:Washington University
address:
name:Department of Genetics, Washington University, St Louis, USA
type:PostalAddress
type:Organization
name:Siteman Cancer Center, Washington University
address:
name:Siteman Cancer Center, Washington University, St Louis, USA
type:PostalAddress
type:Organization
name:The Genome Institute, Washington University
address:
name:The Genome Institute, Washington University, St Louis, USA
type:PostalAddress
type:Organization
name:T J Ley
affiliation:
name:Washington University
address:
name:Department of Internal Medicine, Division of Oncology, Washington University, St Louis, USA
type:PostalAddress
type:Organization
name:Washington University
address:
name:Department of Genetics, Washington University, St Louis, USA
type:PostalAddress
type:Organization
name:Siteman Cancer Center, Washington University
address:
name:Siteman Cancer Center, Washington University, St Louis, USA
type:PostalAddress
type:Organization
name:The Genome Institute, Washington University
address:
name:The Genome Institute, Washington University, St Louis, USA
type:PostalAddress
type:Organization
name:T A Graubert
affiliation:
name:Washington University
address:
name:Department of Internal Medicine, Division of Oncology, Washington University, St Louis, USA
type:PostalAddress
type:Organization
name:Siteman Cancer Center, Washington University
address:
name:Siteman Cancer Center, Washington University, St Louis, USA
type:PostalAddress
type:Organization
email:[email protected]
PostalAddress:
name:Department of Internal Medicine, Division of Oncology, Washington University, St Louis, USA
name:Department of Genetics, Washington University, St Louis, USA
name:Siteman Cancer Center, Washington University, St Louis, USA
name:The Genome Institute, Washington University, St Louis, USA
name:The Genome Institute, Washington University, St Louis, USA
name:Department of Internal Medicine, Division of Oncology, Washington University, St Louis, USA
name:Department of Internal Medicine, Division of Oncology, Washington University, St Louis, USA
name:The Genome Institute, Washington University, St Louis, USA
name:The Genome Institute, Washington University, St Louis, USA
name:The Genome Institute, Washington University, St Louis, USA
name:The Genome Institute, Washington University, St Louis, USA
name:The Genome Institute, Washington University, St Louis, USA
name:The Genome Institute, Washington University, St Louis, USA
name:Division of Biostatistics, Washington University, St Louis, USA
name:Department of Internal Medicine, Division of Oncology, Washington University, St Louis, USA
name:Siteman Cancer Center, Washington University, St Louis, USA
name:Department of Internal Medicine, Division of Oncology, Washington University, St Louis, USA
name:Siteman Cancer Center, Washington University, St Louis, USA
name:Department of Genetics, Washington University, St Louis, USA
name:Siteman Cancer Center, Washington University, St Louis, USA
name:The Genome Institute, Washington University, St Louis, USA
name:Department of Genetics, Washington University, St Louis, USA
name:Siteman Cancer Center, Washington University, St Louis, USA
name:The Genome Institute, Washington University, St Louis, USA
name:Department of Internal Medicine, Division of Oncology, Washington University, St Louis, USA
name:Department of Genetics, Washington University, St Louis, USA
name:Siteman Cancer Center, Washington University, St Louis, USA
name:The Genome Institute, Washington University, St Louis, USA
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