期刊
CANCER CELL
卷 27, 期 4, 页码 502-515出版社
CELL PRESS
DOI: 10.1016/j.ccell.2015.03.009
关键词
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资金
- Gabrielle's Angel Fund grant
- Leukemia Lymphoma Society (LLS) Translational Research grant
- Samuel Waxman Cancer Research Center
- MSKCC [P30 CA008748]
- Sackler Center for Biomedical and Physical Sciences
- Conquer Cancer Foundation
- LLS
- [CA172636-01]
- [R01HG006798]
- [R01NS076465]
- [R01CA166835]
Specific combinations of acute myeloid leukemia (AML) disease alleles, including FLT3 and TET2 mutations, confer distinct biologic features and adverse outcome. We generated mice with mutations in Tet2 and Flt3, which resulted in fully penetrant, lethal AML. Multipotent Tet2(-/-); Flt3(ITD) progenitors (LSK CD48(+)CD150(-)) propagate disease in secondary recipients and were refractory to standard AML chemotherapy and FLT3-targeted therapy. Flt3(ITD) mutations and Tet2 loss cooperatively remodeled DNA methylation and gene expression to an extent not seen with either mutant allele alone, including at the Gata2 locus. Re-expression of Gata2 induced differentiation in AML stem cells and attenuated leukemogenesis. TET2 and FLT3mutations cooperatively induce AML, with a defined leukemia stem cell population characterized by site-specific changes in DNA methylation and gene expression.
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