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 1α (HIF1α) are sufficient to prime leukemia cells for subsequent aggressive growth. In agreement with this, HIF1α is highly expressed in A/E-positive AML patients and strongly predicts inferior outcomes, regardless of gene mutations. Co-expression of A/E and HIF1α in leukemia cells causes a higher cell proliferation rate in vitro and more serious leukemic status in mice. Mechanistically, A/E and HIF1α form a positive regulatory circuit and cooperate to transactivate DNMT3a gene leading to DNA hypermethylation. Pharmacological or genetic interventions in the A/E-HIF1α loop results in DNA hypomethylation, a re-expression of hypermethylated tumor-suppressor p15INK4b and the blockage of leukemia growth. Thus high HIF1α expression serves as a reliable marker, which identif
AML1/ETO cooperates with HIF1α to promote leukemogenesis through DNMT3a transactivation / Gao, Xn; Yan, F; Lin, J; Gao, L; Lu, Xl; Wei, Sc; Shen, N; Pang, Jx; Ning, Qy; Komeno, Y; Deng, Al; Xu, Yh; Shi, Jl; Li, Yh; Zhang, De; Nervi, Clara; Liu, Sj; Yu, L.. - In: LEUKEMIA. - ISSN 0887-6924. - STAMPA. - 29:8(2015), pp. 1730-1740. [10.1038/leu.2015.56]
AML1/ETO cooperates with HIF1α to promote leukemogenesis through DNMT3a transactivation
NERVI, Clara;
2015
Abstract
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 1α (HIF1α) are sufficient to prime leukemia cells for subsequent aggressive growth. In agreement with this, HIF1α is highly expressed in A/E-positive AML patients and strongly predicts inferior outcomes, regardless of gene mutations. Co-expression of A/E and HIF1α in leukemia cells causes a higher cell proliferation rate in vitro and more serious leukemic status in mice. Mechanistically, A/E and HIF1α form a positive regulatory circuit and cooperate to transactivate DNMT3a gene leading to DNA hypermethylation. Pharmacological or genetic interventions in the A/E-HIF1α loop results in DNA hypomethylation, a re-expression of hypermethylated tumor-suppressor p15INK4b and the blockage of leukemia growth. Thus high HIF1α expression serves as a reliable marker, which identifFile | Dimensione | Formato | |
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