期刊
LEUKEMIA
卷 29, 期 8, 页码 1730-1740出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2015.56
关键词
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资金
- National Institutes of Health/National Cancer Institute [R01CA149623, R01CA104509, R21CA155915]
- Hormel Foundation
- National Natural Science Foundation of China [90919044, 30971297, 81170518, 81000221, 81370010, 81171820, 81370635]
- National Public Health Grand Research Foundation [201202017]
- Capital Public Health Project [Z111107067311070]
- Capital Medical Development Scientific Research Fund [2007-2040]
- Beijing Natural Science Foundation [7122169, 7112126]
- Beijing New Stars Program of Science and Technology [2010B075]
- Italian Association for Cancer Research [IG-11949]
The mechanisms by which AML1/ETO (A/E) fusion protein induces leukemogenesis in acute myeloid leukemia (AML) without mutagenic events remain elusive. Here we show that interactions between A/E and hypoxia-inducible factor 1 alpha ( HIF1 alpha) are sufficient to prime leukemia cells for subsequent aggressive growth. In agreement with this, HIF1 alpha is highly expressed in A/E-positive AML patients and strongly predicts inferior outcomes, regardless of gene mutations. Co-expression of A/E and HIF1 alpha in leukemia cells causes a higher cell proliferation rate in vitro and more serious leukemic status in mice. Mechanistically, A/E and HIF1 alpha form a positive regulatory circuit and cooperate to transactivate DNMT3 alpha gene leading to DNA hypermethylation. Pharmacological or genetic interventions in the A/E-HIF1 alpha loop results in DNA hypomethylation, a re-expression of hypermethylated tumor-suppressor p15(INK4b) and the blockage of leukemia growth. Thus high HIF1 alpha expression serves as a reliable marker, which identifies patients with a poor prognosis in an otherwise prognostically favorable AML group and represents an innovative therapeutic target in high-risk A/E-driven leukemia.
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