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Germline DNMT3A mutation in familial acute myeloid leukaemia.

Authors
  • DiNardo, Courtney D1
  • Beird, Hannah C2
  • Estecio, Marcos3, 4
  • Hardikar, Swanand3, 4
  • Takahashi, Koichi1
  • Bannon, Sarah A5
  • Borthakur, Gautam1
  • Jabbour, Elias1
  • Gumbs, Curtis2
  • Khoury, Joseph D4
  • Routbort, Mark4
  • Gong, Ting3, 4
  • Kondo, Kimie3, 4
  • Kantarjian, Hagop1
  • Garcia-Manero, Guillermo1
  • Chen, Taiping3, 4
  • Futreal, P Andrew2, 6
  • 1 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 2 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 3 Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4 Center for Cancer Epigenetics, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5 Department of Clinical Cancer Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 6 Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Type
Published Article
Journal
Epigenetics
Publisher
Landes Bioscience
Publication Date
May 01, 2021
Volume
16
Issue
5
Pages
567–576
Identifiers
DOI: 10.1080/15592294.2020.1809871
PMID: 32856987
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Acute myeloid leukaemia (AML) is a heterogeneous myeloid malignancy characterized by recurrent clonal events, including mutations in epigenetically relevant genes such as DNMT3A, ASXL1, IDH1/2, and TET2. Next-generation sequencing analysis of a mother and son pair who both developed adult-onset diploid AML identified a novel germline missense mutation DNMT3A p.P709S. The p.P709S protein-altering variant resides in the highly conserved catalytic DNMT3A methyltransferase domain. Functional studies demonstrate that the p.P709S variant confers dominant negative effects when interacting with wildtype DNMT3A. LINE-1 pyrosequencing and reduced representation bisulphite sequencing (RBBS) analysis demonstrated global DNA hypomethylation in germline samples, not present in the leukaemic samples. Somatic acquisition of IDH2 p.R172K mutations, in concert with additional acquired clonal DNMT3A events in both patients at the time of AML diagnosis, confirms the important pathogenic interaction of epigenetically active genes, and implies a strong selection and regulation of methylation in leukaemogenesis. Improved characterization of germline mutations may enable us to better predict malignant clonal evolution, improving our ability to provide customized treatment or future preventative strategies.

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