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

J Exp Med 2016 Jan 14;213(1):25-34. Epub 2015 Dec 14.

Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136 Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136 Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136

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.

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http://dx.doi.org/10.1084/jem.20150524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710200PMC
January 2016

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