期刊
LEUKEMIA
卷 29, 期 10, 页码 2075-2085出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2015.102
关键词
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资金
- National Health and Medical Research Council of Australia [604303]
- Mater Foundation
- Australian Based Biomedical Fellowship from the National Health and Medical Research Council [488821]
- [1044091]
- [1033736]
- Div Of Chem, Bioeng, Env, & Transp Sys
- Directorate For Engineering [1033736] Funding Source: National Science Foundation
Hypoxia-inducible factor (HIF)-1 alpha accumulation promotes hematopoietic stem cells' quiescence and is necessary to maintain their self-renewal. However, the role of HIF-2 alpha in hematopoietic cells is less clear. We investigated the role of HIF-2 alpha in leukemia and lymphoma cells. HIF-2 alpha expression was high in subsets of human and mouse leukemia and lymphoma cells, whereas it was low in normal bone marrow leukocytes. To investigate the role of HIF-2 alpha, we transduced human HIF-2 alpha cDNA in mouse syngeneic models of myeloid preleukemia and a transgenic model of B lymphoma. Ectopic expression of HIF-2 alpha accelerated leukemia cell proliferation in vitro. Mice transplanted with cells transduced with HIF-2 alpha died significantly faster of leukemia or B lymphoma than control mice transplanted with empty vector-transduced cells. Conversely, HIF-2 alpha knockdown in human myeloid leukemia HL60 cells decreased proliferation in vitro and significantly prolonged animal survival following transplantation. In human acute myeloid leukemia (AML), HIF-2 alpha mRNA was significantly elevated in several subsets such as the t(15; 17), inv(16), complex karyotype and favorable cytogenetic groups. However, patients with high HIF-2 alpha expression had a trend to higher disease-free survival in univariate analysis. The different effects of HIF-2 alpha overexpression in mouse models of leukemia and human AML illustrates the complexity of this mutliclonal disease.
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