Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model.
Author
Summary, in English
Biallelic CEBPA mutations and FLT3 length mutations are frequently identified in human acute myeloid leukemia (AML) with normal cytogenetics. However, the molecular and cellular mechanisms of oncogene cooperation remain unclear due to a lack of disease models. We have generated an AML mouse model using knockin mouse strains to study cooperation of internal tandem duplication (ITD) mutation in the Flt3 gene with commonly observed C/EBPα mutations. This study provides evidence that FLT3 ITD cooperates in leukemogenesis by enhancing the generation of leukemia-initiating granulocyte-monocyte progenitors (GMP) otherwise prevented by a block in differentiation and skewed lineage priming induced by biallelic C/EBPα mutations. These cellular changes are accompanied by an upregulation of hematopoietic stem cell and STAT5 target genes. By gene expression analysis in premalignant populations we further show a role of FLT3 ITD in activating genes involved in survival/transformation and chemoresistance. Both multipotent progenitors (MPP) and GMP cells contain the potential to induce AML similar to corresponding cells in human AML samples showing that this model resembles human disease.Leukemia accepted article preview online, 9 February 2012; doi:10.1038/leu.2012.37.
Department/s
- Stem Cell Center
- Division of Molecular Medicine and Gene Therapy
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
Publishing year
2012
Language
English
Pages
1527-1536
Publication/Series
Leukemia
Volume
26
Issue
7
Links
Document type
Journal article
Publisher
Nature Publishing Group
Topic
- Cancer and Oncology
Status
Published
ISBN/ISSN/Other
- ISSN: 1476-5551