title: Dicer1 imparts essential survival cues in Notch-driven T-ALL via miR-21-mediated tumor suppressor Pdcd4 repression.
abstract: The modulatory function of individual microRNAs (miRNAs) in Notch-driven T-cell acute lymphoblastic leukemias (T-ALLs) has recently been established. Although protumorigenic and tumor-suppressive miRNAs are implicated in disease onset in murine models of Notch-driven T-cell leukemia, whether Dicer1-processed miRNAs are essential for Notch-driven T-ALL is currently unknown. Here we used conditional and inducible genetic loss-of-function approaches to test whether the development and maintenance of Notch-driven T-ALL was dependent on Dicer1 function. Mice with specific inactivation of both Dicer1 alleles in the T-cell lineage did not develop Notch-driven T-ALL. In contrast, loss of 1 functional Dicer1 allele did not significantly perturb T-ALL onset and tumor progression. Inducible inactivation of Dicer1 in early stage polyclonal T-ALL cells was sufficient to abrogate T-ALL progression in leukemic mice, whereas late-stage monoclonal T-ALL cells were counterselected against loss of Dicer1. Lineage-tracing experiments revealed that Dicer1 deficiency led to the induction of apoptosis in T-ALL cells, whereas cell cycle progression remained unaltered. Through microarray-based miRNA profiling, we identified miR-21 as a previously unrecognized miRNA deregulated in both mouse and human T-ALL. Herein, we demonstrate that miR-21 regulates T-ALL cell survival via repression of the tumor suppressor Pdcd4.
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, Swiss Experimental Cancer Research Institute, Lausanne, Switzerland.
authors.forename: Fabian
authors.initials: F
authors.lastname: Junker
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, Swiss Experimental Cancer Research Institute, Lausanne, Switzerland.
authors.forename: Antoine
authors.initials: A
authors.lastname: Chabloz
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, Swiss Experimental Cancer Research Institute, Lausanne, Switzerland.
authors.forename: Ute
authors.initials: U
authors.lastname: Koch
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, Swiss Experimental Cancer Research Institute, Lausanne, Switzerland.
authors.forename: Freddy
authors.identifier: http://orcid.org/0000-0003-4315-4045
authors.initials: F
authors.lastname: Radtke
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism; D043244:Ribonuclease III / Q000378:metabolism*; D014162:Transfection
chemical_list: D051017:Apoptosis Regulatory Proteins; C524940:MIRN21 microRNA, human; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; C114487:PDCD4 protein, human; C498443:Pdcd4 protein, mouse; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D051880:Receptors, Notch; D043244:Ribonuclease III