Integrative genetic analysis of mouse and human AML identifies cooperating disease alleles

J Exp Med. 2016 Jan 11;213(1):25-34. doi: 10.1084/jem.20150524. Epub 2015 Dec 14.


t(8;21) is one of the most frequent chromosomal abnormalities observed in acute myeloid leukemia (AML). However, expression of AML1-ETO is not sufficient to induce transformation in vivo. Consistent with this observation, patients with this translocation harbor additional genetic abnormalities, suggesting a requirement for cooperating mutations. To better define the genetic landscape in AML and distinguish driver from passenger mutations, we compared the mutational profiles of AML1-ETO-driven mouse models of leukemia with the mutational profiles of human AML patients. We identified TET2 and PTPN11 mutations in both mouse and human AML and then demonstrated the ability of Tet2 loss and PTPN11 D61Y to initiate leukemogenesis in concert with expression of AML1-ETO in vivo. This integrative genetic profiling approach allowed us to accurately predict cooperating events in t(8;21)(+) AML in a robust and unbiased manner, while also revealing functional convergence in mouse and human AML.

Publication types

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

MeSH terms

  • Alleles*
  • Animals
  • Cell Transformation, Neoplastic / genetics
  • Chromosomes, Human, Pair 21
  • Chromosomes, Human, Pair 8
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Disease Models, Animal
  • Epistasis, Genetic*
  • Gene Expression Regulation, Leukemic
  • Gene Knockout Techniques
  • Genomics / methods*
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Mice
  • Mutation
  • Oncogene Proteins, Fusion / genetics
  • Phenotype
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
  • RUNX1 Translocation Partner 1 Protein
  • Translocation, Genetic


  • AML1-ETO fusion protein, human
  • Core Binding Factor Alpha 2 Subunit
  • Oncogene Proteins, Fusion
  • RUNX1 Translocation Partner 1 Protein
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11