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Integrative genetic analysis of mouse and human AML identifies cooperating disease alleles
- Source :
- The Journal of Experimental Medicine
- Publication Year :
- 2015
-
Abstract
- Hatlen et al. provide an integrative analysis of the mutational landscape of mouse and human AML and identify functionally relevant cooperation between AML1-ETO and PTPN11 D61Y. Based on these findings, they generate a novel mouse model of t(8;21)+ AML.<br />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.
- Subjects :
- 0301 basic medicine
Myeloid
Oncogene Proteins, Fusion
Chromosomes, Human, Pair 21
Immunology
Chromosomal translocation
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Biology
medicine.disease_cause
Translocation, Genetic
03 medical and health sciences
Gene Knockout Techniques
Mice
RUNX1 Translocation Partner 1 Protein
hemic and lymphatic diseases
medicine
Immunology and Allergy
Animals
Humans
Allele
neoplasms
Alleles
Research Articles
Genetics
Mutation
Gene Expression Regulation, Leukemic
Brief Definitive Report
Myeloid leukemia
Epistasis, Genetic
Genomics
medicine.disease
Phenotype
Leukemia
Disease Models, Animal
Leukemia, Myeloid, Acute
030104 developmental biology
medicine.anatomical_structure
Cell Transformation, Neoplastic
Core Binding Factor Alpha 2 Subunit
Chromosomes, Human, Pair 8
Subjects
Details
- ISSN :
- 15409538
- Volume :
- 213
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- The Journal of experimental medicine
- Accession number :
- edsair.doi.dedup.....697a44873d55ac31b7def89a1274549c