AML1/ETO cooperates with HIF1α to promote leukemogenesis through DNMT3a transactivation.
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.
1] Department of Hematology, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China [2] The Hormel Institute, University of Minnesota, Austin, MN, USA.
X N
XN
Gao
The Hormel Institute, University of Minnesota, Austin, MN, USA.
F
F
Yan
Institute of Basic Medicine, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China.
J
J
Lin
Department of Hematology, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China.
L
L
Gao
Department of Hematology, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China.
X L
XL
Lu
The Hormel Institute, University of Minnesota, Austin, MN, USA.
S C
SC
Wei
The Hormel Institute, University of Minnesota, Austin, MN, USA.
N
N
Shen
The Hormel Institute, University of Minnesota, Austin, MN, USA.
J X
JX
Pang
Department of Hematology, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China.
Q Y
QY
Ning
Department of Pathology and Division of Biological Sciences, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA.
Y
Y
Komeno
Department of Hematology, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China.
A L
AL
Deng
Department of Hematology, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China.
Y H
YH
Xu
Department of Hematology, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China.
J L
JL
Shi
Department of Hematology, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China.
Y H
YH
Li
Department of Pathology and Division of Biological Sciences, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA.
D E
DE
Zhang
Department of Medical Surgical Sciences and Biotechnologies, University of Rome 'La Sapienza', Latina, Italy.
C
C
Nervi
The Hormel Institute, University of Minnesota, Austin, MN, USA.
S J
SJ
Liu
Department of Hematology, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China.
L
L
Yu
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D047369:Chromatin Immunoprecipitation; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D005434:Flow Cytometry; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D000075142:RUNX1 Translocation Partner 1 Protein; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D000075142:RUNX1 Translocation Partner 1 Protein; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A