title: miRNA-130a targets ATG2B and DICER1 to inhibit autophagy and trigger killing of chronic lymphocytic leukemia cells.
abstract: Toxicity and relapses from the immunochemotherapy used to treat chronic lymphocytic leukemia (CLL) prompt continued interest in gentle but effective targeted treatment options for the mainly elderly population suffering from this disease. Here, we report the definition of critical CLL cell survival pathways that can be targeted by ectopic reexpression of the miRNA genes miR-130a and miR-143 which are widely downregulated in CLL. Notably, miR-130a inhibited autophagy by reducing autophagosome formation, an effect mediated by downregulation of the genes ATG2B and DICER1, the latter of which is a major component of the miRNA silencing machinery. In support of the concept of a fundamental connection between miRNA disregulation and altered autophagic flux in this cancer, we showed that RNA interference-mediated knockdown of DICER1 expression was sufficient to reduce autophagy in primary or established cultures of CLL cells. Together, our findings show that miR-130a modulates cell survival programs by regulating autophagic flux, and they define roles for miR-130a and Dicer1 in a regulatory feedback loop that mediates CLL cell survival.
authors.affiliation: University of Heidelberg, Heidelberg, Germany.
authors.forename: Valentina
authors.initials: V
authors.lastname: Kovaleva
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Mora
authors.forename: Yoon Jung
authors.initials: YJ
authors.lastname: Park
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.forename: Abhilash I
authors.initials: AI
authors.lastname: Chiramel
authors.forename: Ralf
authors.initials: R
authors.lastname: Bartenschlager
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Stephan
authors.initials: S
authors.lastname: Stilgenbauer
authors.forename: Armin
authors.initials: A
authors.lastname: Pscherer
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.forename: Martina
authors.initials: M
authors.lastname: Seiffert
mesh_terms: D001343:Autophagy; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000473:pathology*; D035683:MicroRNAs / Q000502:physiology*; D043244:Ribonuclease III / Q000235:genetics*; D033921:Vesicular Transport Proteins
chemical_list: C572313:ATG2B protein, human; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; C554019:MIRN130 microRNA, human; C542359:MIRN143 microRNA, human; D035683:MicroRNAs; D033921:Vesicular Transport Proteins; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases