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

Leukemia
X N GaoLi Yu

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.

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Citations

Mar 10, 2016·Frontiers in Oncology·Margaux DeynouxFrédéric Mazurier
Jan 30, 2016·American Journal of Hematology·Paolo BernasconiCeleste Calvello
Aug 27, 2016·Frontiers in Oncology·Garland Michael UpchurchRene Opavsky
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Apr 19, 2017·Oncotarget·Marta IrigoyenEdurne Berra
Aug 27, 2016·Medical Science Monitor : International Medical Journal of Experimental and Clinical Research·Sai HuangLi Yu
Feb 6, 2017·Journal of Hematology & Oncology·Yan LiLi Yu
Sep 3, 2019·Frontiers in Pharmacology·Vladimir Alexandrovich MitkevichAlexander Alexander Makarov
Jan 19, 2019·International Journal of Molecular Sciences·Emiel van der Kouwe, Philipp Bernhard Staber
Sep 6, 2019·Journal of Oncology·Paolo Bernasconi, Oscar Borsani
Jul 20, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Na ShenShujun Liu
Jul 3, 2021·International Journal of Environmental Research and Public Health·Steffen MuellerShujun Liu
Apr 19, 2018·ACS Applied Materials & Interfaces·Na ShenShujun Liu
Dec 19, 2021·Experimental & Molecular Medicine·Erna YangLi Yu

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