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 p15(INK4b) and the blockage of leukemia growth. Thus high HIF1α 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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Blotting, Western
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Cell Proliferation
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Cell Transformation, Neoplastic / pathology*
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Chromatin Immunoprecipitation
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Core Binding Factor Alpha 2 Subunit / genetics
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Core Binding Factor Alpha 2 Subunit / metabolism*
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DNA (Cytosine-5-)-Methyltransferases / genetics*
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DNA Methylation*
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DNA Methyltransferase 3A
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Flow Cytometry
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Immunoenzyme Techniques
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Leukemia, Myeloid, Acute / genetics*
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Leukemia, Myeloid, Acute / metabolism
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Leukemia, Myeloid, Acute / pathology*
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Mice
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism*
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Promoter Regions, Genetic / genetics
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RNA, Messenger / genetics
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RUNX1 Translocation Partner 1 Protein
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Transcriptional Activation
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
Substances
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AML1-ETO fusion protein, human
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Core Binding Factor Alpha 2 Subunit
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DNMT3A protein, human
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Dnmt3a protein, mouse
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Oncogene Proteins, Fusion
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RNA, Messenger
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RUNX1 Translocation Partner 1 Protein
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DNA (Cytosine-5-)-Methyltransferases
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DNA Methyltransferase 3A