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


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.

DOI: 10.1084/jem.20150524

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@inproceedings{Hatlen2016IntegrativeGA, title={Integrative genetic analysis of mouse and human AML identifies cooperating disease alleles}, author={Megan A. Hatlen and Kanika Arora and Vladimir Vacic and Ewa Grabowska and Willey Liao and Bridget Riley-Gillis and Dayna M. Oschwald and Lan Wang and Jacob E. Joergens and Alan Shih and Franck Rapaport and Shengqing Gu and Francesca Voza and Takashi Asai and Benjamin G . Neel and Michael G Kharas and Mithat Gonen and Ross L. Levine and Stephen D. Nimer}, booktitle={The Journal of experimental medicine}, year={2016} }