title: Intronic miR-3151 within BAALC drives leukemogenesis by deregulating the TP53 pathway.
abstract: The BAALC/miR-3151 locus on chromosome 8q22 contains both the BAALC gene (for brain and acute leukemia, cytoplasmic) and miR-3151, which is located in intron 1 of BAALC. Older acute myeloid leukemia (AML) patients with high expression of both miR-3151 and the BAALC mRNA transcript have a low survival prognosis, and miR-3151 and BAALC expression is associated with poor survival independently of each other. We found that miR-3151 functioned as the oncogenic driver of the BAALC/miR-3151 locus. Increased production of miR-3151 reduced the apoptosis and chemosensitivity of AML cell lines and increased leukemogenesis in mice. Disruption of the TP53-mediated apoptosis pathway occurred in leukemia cells overexpressing miR-3151 and the miR-3151 bound to the 3' untranslated region of TP53. In contrast, BAALC alone had only limited oncogenic activity. We found that miR-3151 contains its own regulatory element, thus partly uncoupling miR-3151 expression from that of the BAALC transcript. Both genes were bound and stimulated by a complex of the transcription factors SP1 and nuclear factor κB (SP1/NF-κB). Disruption of SP1/NF-κB binding reduced both miR-3151 and BAALC expression. However, expression of only BAALC, but not miR-3151, was stimulated by the transcription factor RUNX1, suggesting a mechanism for the partly discordant expression of miR-3151 and BAALC observed in AML patients. Similar to the AML cells, in melanoma cell lines, overexpression of miR-3151 reduced the abundance of TP53, and knockdown of miR-3151 increased caspase activity, whereas miR-3151 overexpression reduced caspase activity. Thus, this oncogenic miR-3151 may also have a role in solid tumors.
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Eisfeld
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schwind
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Patel
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Huang
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Santhanam
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Walker
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Markowitz
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Hoag
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Tiina M
authors.initials: TM
authors.lastname: Jarvinen
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Leffel
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Danilo
authors.initials: D
authors.lastname: Perrotti
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Carson
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
mesh_terms: D000818:Animals; D017209:Apoptosis; D001897:Boronic Acids / Q000737:chemistry; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002875:Chromosomes / Q000648:ultrastructure; D019295:Computational Biology; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D003582:Cytogenetics; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007438:Introns; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D008297:Male; D008545:Melanoma / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D010641:Phenotype; D011719:Pyrazines / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C442828:BAALC protein, human; D001897:Boronic Acids; D050676:Core Binding Factor Alpha 2 Subunit; C000593307:MIRN3151 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011719:Pyrazines; D012333:RNA, Messenger; C493728:RUNX1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000069286:Bortezomib
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