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Phosphorylation of BECLIN-1 by BCR-ABL suppresses autophagy in chronic myeloid leukemia.
Yu, Chuanjiang; Gorantla, Sivahari P; Müller-Rudorf, Alina; Müller, Tony A; Kreutmair, Stefanie; Albers, Corinna; Jakob, Lena; Lippert, Lena J; Yue, Zhenyu; Engelhardt, Monika; Follo, Marie; Zeiser, Robert; Huber, Tobias B; Duyster, Justus; Illert, Anna L.
Afiliación
  • Yu C; Department of Internal Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Gorantla SP; Department of Internal Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Müller-Rudorf A; Department of Internal Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Müller TA; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Kreutmair S; Department of Internal Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Albers C; Department of Internal Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Jakob L; Department of Medicine, Klinikum rechts der Isar, Technical University München, München, Germany.
  • Lippert LJ; Department of Internal Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Yue Z; Department of Internal Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Engelhardt M; Department of Neurology and Neuroscience, Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY, USA.
  • Follo M; Department of Internal Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Zeiser R; Department of Internal Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Huber TB; Department of Internal Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Duyster J; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Illert AL; Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Haematologica ; 105(5): 1285-1293, 2020 05.
Article en En | MEDLINE | ID: mdl-31399521
Autophagy is a genetically regulated process of adaptation to metabolic stress and was recently shown to be involved in the treatment response of chronic myeloid leukemia (CML). However, in vivo data are limited and the molecular mechanism of autophagy regulators in the process of leukemogenesis is not completely understood. Here we show that Beclin-1 knockdown, but not Atg5 deletion in a murine CML model leads to a reduced leukemic burden and results in a significantly prolonged median survival of targeted mice. Further analyses of murine cell lines and primary patient material indicate that active BCR-ABL directly interacts with BECLIN-1 and phosphorylates its tyrosine residues 233 and 352, resulting in autophagy suppression. By using phosphorylation-deficient and phosphorylation-mimic mutants, we identify BCR-ABL induced BECLIN-1 phosphorylation as a crucial mechanism for BECLIN-1 complex formation: interaction analyses exhibit diminished binding of the positive autophagy regulators UVRAG, VPS15, ATG14 and VPS34 and enhanced binding of the negative regulator Rubicon to BCR-ABL-phosphorylated BECLIN-1. Taken together, our findings show interaction of BCR-ABL and BECLIN-1 thereby highlighting the importance of BECLIN-1-mediated autophagy in BCR-ABL+ cells.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mielógena Crónica BCR-ABL Positiva / Proteínas de Fusión bcr-abl Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Haematologica Año: 2020 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Italia
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mielógena Crónica BCR-ABL Positiva / Proteínas de Fusión bcr-abl Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Haematologica Año: 2020 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Italia