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

Megan A. Hatlen, Kanika Arora, Vladimir Vacic, Ewa A. Grabowska, Willey Liao, Bridget Riley-Gillis, Dayna M. Oschwald, Lan Wang, Jacob E. Joergens, Alan H. Shih, Franck Rapaport, Shengqing Gu, Francesca Voza, Takashi Asai, Benjamin G. Neel, Michael G. Kharas, Mithat Gonen, Ross L. Levine, Stephen D. Nimer

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)25-34
Number of pages10
JournalJournal of Experimental Medicine
Volume213
Issue number1
DOIs
StatePublished - Jan 1 2016

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Hatlen, M. A., Arora, K., Vacic, V., Grabowska, E. A., Liao, W., Riley-Gillis, B., Oschwald, D. M., Wang, L., Joergens, J. E., Shih, A. H., Rapaport, F., Gu, S., Voza, F., Asai, T., Neel, B. G., Kharas, M. G., Gonen, M., Levine, R. L., & Nimer, S. D. (2016). Integrative genetic analysis of mouse and human AML identifies cooperating disease alleles. Journal of Experimental Medicine, 213(1), 25-34. https://doi.org/10.1084/jem.20150524