期刊
EXPERIMENTAL HEMATOLOGY
卷 42, 期 2, 页码 101-113出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.exphem.2013.10.005
关键词
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资金
- St. Baldrick's Foundation (Post-Doctoral Fellowship for Childhood Cancer Research Award)
- Leukemia and Lymphoma Society (Translational Research Program Grant, Scholar in Clinical Research Award)
- National Cancer Institute [K23 CA111728, R01CA90668, P01CA70970]
- Damon Runyon Cancer Research Foundation (Clinical Investigator Award)
- Giant Food Children's Cancer Research Fund
Cytoplasmic nucleophosmin (NPMc(+)) mutations and FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations are two of the most common known molecular alterations in acute myeloid leukemia (AML); they frequently occur together, suggesting cooperative leukemogenesis. To explore the specific relationship between NPMc+ and FLT3/ITD in vivo, we crossed Flt3/ITD knock-in mice with transgenic NPMc+ mice. Mice with both mutations develop a transplantable leukemia of either myeloid or lymphoid lineage, definitively demonstrating cooperation between Flt3/ITD and NPMc+. In mice with myeloid leukemia, functionally significant loss of heterozygosity of the wild-type Flt3 allele is common, similar to what is observed in human FLT3/ITD+ AML, providing further in vivo evidence of the importance of loss of wild-type FLT3 in leukemic initiation and progression. Additionally, in vitro clonogenic assays reveal that the combination of Flt3/ITD and NPMc+ mutations causes a profound monocytic expansion, in excess of that seen with either mutation alone consistent with the predominance of myelomonocytic phenotype in human FLT3/ITD+/NPMc+ AML. This in vivo model of Flt3/ITD+/NPMc+ leukemia closely recapitulates human disease and will therefore serve as a tool for the investigation of the biology of this common disease entity. (C) 2014 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.
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