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, sugg...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of experimental medicine 2016-01, Vol.213 (1), p.25-34
Main Authors: Hatlen, Megan A, Arora, Kanika, Vacic, Vladimir, Grabowska, Ewa A, Liao, Willey, Riley-Gillis, Bridget, Oschwald, Dayna M, Wang, Lan, Joergens, Jacob E, Shih, Alan H, Rapaport, Franck, Gu, Shengqing, Voza, Francesca, Asai, Takashi, Neel, Benjamin G, Kharas, Michael G, Gonen, Mithat, Levine, Ross L, Nimer, Stephen D
Format: Article
Language:English
Subjects:
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
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20150524