Functional genomic landscape of acute myeloid leukaemia

Nature. 2018 Oct;562(7728):526-531. doi: 10.1038/s41586-018-0623-z. Epub 2018 Oct 17.

Abstract

The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset-accessible through the Beat AML data viewer (Vizome)-that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Core Binding Factor Alpha 2 Subunit / genetics
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • Datasets as Topic
  • Exome / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / genetics*
  • Genome, Human / genetics*
  • Genomics*
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / metabolism
  • Male
  • Molecular Targeted Therapy
  • Nuclear Proteins / genetics
  • Proto-Oncogene Proteins / genetics
  • Repressor Proteins / genetics
  • Sequence Analysis, RNA
  • Serine-Arginine Splicing Factors / genetics

Substances

  • BCOR protein, human
  • Core Binding Factor Alpha 2 Subunit
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • RUNX1 protein, human
  • Repressor Proteins
  • nucleophosmin
  • SRSF2 protein, human
  • Serine-Arginine Splicing Factors
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A