Abstract
The oncogenic fusion protein AML1-ETO, also known as RUNX1-RUNX1T1 is generated by the t(8;21)(q22;q22) translocation, one of the most frequent chromosomal rearrangements in acute myeloid leukemia (AML). Identifying the genes that cooperate with or are required for the oncogenic activity of this chimeric transcription factor remains a major challenge. Our previous studies showed that Drosophila provides a genuine model to study how AML1-ETO promotes leukemia. Here, using an in vivo RNA interference screen for suppressors of AML1-ETO activity, we identified pontin/RUVBL1 as a gene required for AML1-ETO-induced lethality and blood cell proliferation in Drosophila. We further show that PONTIN inhibition strongly impaired the growth of human t(8;21)(+) or AML1-ETO-expressing leukemic blood cells. Interestingly, AML1-ETO promoted the transcription of PONTIN. Moreover, transcriptome analysis in Kasumi-1 cells revealed a strong correlation between PONTIN and AML1-ETO gene signatures and demonstrated that PONTIN chiefly regulated the expression of genes implicated in cell cycle progression. Concordantly, PONTIN depletion inhibited leukemic self-renewal and caused cell cycle arrest. All together our data suggest that the upregulation of PONTIN by AML1-ETO participate in the oncogenic growth of t(8;21) cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATPases Associated with Diverse Cellular Activities
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Animals
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism
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Blotting, Western
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Cycle
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Cell Proliferation*
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Chromosomes, Human, Pair 21 / genetics
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Chromosomes, Human, Pair 8 / genetics
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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 Helicases / antagonists & inhibitors
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DNA Helicases / genetics
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DNA Helicases / metabolism*
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Drosophila melanogaster / genetics*
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Drosophila melanogaster / growth & development
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Female
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic*
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Humans
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Leukemia, Myeloid, Acute / etiology*
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Leukemia, Myeloid, Acute / metabolism
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Leukemia, Myeloid, Acute / pathology
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Male
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Oligonucleotide Array Sequence Analysis
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism*
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RNA, Messenger / genetics
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RNA, Small Interfering / 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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Translocation, Genetic
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Tumor Cells, Cultured
Substances
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AML1-ETO fusion protein, human
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Biomarkers, Tumor
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Carrier Proteins
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Core Binding Factor Alpha 2 Subunit
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Oncogene Proteins, Fusion
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RNA, Messenger
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RNA, Small Interfering
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RUNX1 Translocation Partner 1 Protein
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ATPases Associated with Diverse Cellular Activities
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DNA Helicases
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RUVBL1 protein, human
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RUVBL2 protein, human