AML1/ETO cooperates with HIF1 alpha to promote leukemogenesis through DNMT3 alpha transactivation

作者：Gao, X. N.; Yan, F.; Lin, J.; Gao, L.; Lu, X. L.; Wei, S. C.; Shen, N.; Pang, J. X.; Ning, Q. Y.; Komeno, Y.; Deng, A. L.; Xu, Y. H.; Shi, J. L.; Li, Y. H.; Zhang, D. E.; Nervi, C.; Liu, S. J.^*; Yu, L.

来源：Leukemia, 2015, 29(8): 1730-1740.

DOI：10.1038/leu.2015.56

• ACUTE MYELOID-LEUKEMIA
• HYPOXIA-INDUCIBLE FACTOR-1-ALPHA
• FUSION PROTEIN
• STEM-CELLS
• TUMOR-SUPPRESSOR
• KIT MUTATIONS
• DNA-BINDING
• AML1-ETO
• T(8/21)
• EXPRESSION

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.

• 出版日期2015-8
• 单位中国人民解放军总医院