AML1/ETO cooperates with HIF1α to promote leukemogenesis through DNMT3a transactivation

X. N. Gao, Fei Yan, J. Lin, L. Gao, X. L. Lu, S. C. Wei, N. Shen, J. X. Pang, Q. Y. Ning, Y. Komeno, A. L. Deng, Y. H. Xu, J. L. Shi, Y. H. Li, D. E. Zhang, C. Nervi, Shujun Liu, L. Yu

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1730-1740
Number of pages11
JournalLeukemia
Volume29
Issue number8
DOIs
StatePublished - Aug 7 2015

Bibliographical note

Funding Information:
This work was partially supported by grants from the National Institutes of Health/ National Cancer Institute (R01CA149623, R01CA104509 and R21CA155915), the Hormel Foundation, the National Natural Science Foundation of China (90919044, 30971297, 81170518, 81000221, 81370010, 81171820 and 81370635), the National Public Health Grand Research Foundation (201202017), the Capital Public Health Project (Z111107067311070), the Capital Medical Development Scientific Research Fund (2007–2040), the Beijing Natural Science Foundation (7122169 and 7112126), the Beijing New Stars Program of Science and Technology (2010B075) and the Italian Association for Cancer Research (IG-11949).

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