title: Pontin is a critical regulator for AML1-ETO-induced leukemia.
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.
authors.affiliation: CNRS, CBD UMR5547, Université de Toulouse, UPS, CBD (Centre de Biologie du Développement), Bâtiment 4R3, 118 route de Narbonne, Toulouse, France.
authors.forename: O
authors.initials: O
authors.lastname: Breig
authors.affiliation: CNRS, CBD UMR5547, Université de Toulouse, UPS, CBD (Centre de Biologie du Développement), Bâtiment 4R3, 118 route de Narbonne, Toulouse, France.
authors.forename: S
authors.initials: S
authors.lastname: Bras
authors.affiliation: Northern Institute for Cancer Research, University of Newcastle, Newcastle upon Tyne, UK.
authors.forename: N
authors.initials: N
authors.lastname: Martinez Soria
authors.affiliation: CNRS, CBD UMR5547, Université de Toulouse, UPS, CBD (Centre de Biologie du Développement), Bâtiment 4R3, 118 route de Narbonne, Toulouse, France.
authors.forename: D
authors.initials: D
authors.lastname: Osman
authors.affiliation: Northern Institute for Cancer Research, University of Newcastle, Newcastle upon Tyne, UK.
authors.forename: O
authors.initials: O
authors.lastname: Heidenreich
authors.affiliation: CNRS, CBD UMR5547, Université de Toulouse, UPS, CBD (Centre de Biologie du Développement), Bâtiment 4R3, 118 route de Narbonne, Toulouse, France.
authors.forename: M
authors.identifier: 0000000327288457
authors.initials: M
authors.lastname: Haenlin
authors.affiliation: CNRS, CBD UMR5547, Université de Toulouse, UPS, CBD (Centre de Biologie du Développement), Bâtiment 4R3, 118 route de Narbonne, Toulouse, France.
authors.forename: L
authors.initials: L
authors.lastname: Waltzer
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D049109:Cell Proliferation; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D004265:DNA Helicases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics* / Q000254:growth & development; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D000075142:RUNX1 Translocation Partner 1 Protein; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
chemical_list: C107844:AML1-ETO fusion protein, human; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000075142:RUNX1 Translocation Partner 1 Protein; D000074183:ATPases Associated with Diverse Cellular Activities; D004265:DNA Helicases; C486549:RUVBL1 protein, human; C122079:RUVBL2 protein, human