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Phosphorylation of BECLIN-1 by BCR-ABL suppresses autophagy in chronic myeloid leukemia

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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ferrata Storti Foundation 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193473/
https://www.ncbi.nlm.nih.gov/pubmed/31399521
http://dx.doi.org/10.3324/haematol.2018.212027
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author 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.
author_facet 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.
author_sort Yu, Chuanjiang
collection PubMed
description 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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spelling pubmed-71934732020-05-11 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. Haematologica Articles 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. Ferrata Storti Foundation 2020-05 /pmc/articles/PMC7193473/ /pubmed/31399521 http://dx.doi.org/10.3324/haematol.2018.212027 Text en Copyright© 2020 Ferrata Storti Foundation Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher.
spellingShingle Articles
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.
Phosphorylation of BECLIN-1 by BCR-ABL suppresses autophagy in chronic myeloid leukemia
title Phosphorylation of BECLIN-1 by BCR-ABL suppresses autophagy in chronic myeloid leukemia
title_full Phosphorylation of BECLIN-1 by BCR-ABL suppresses autophagy in chronic myeloid leukemia
title_fullStr Phosphorylation of BECLIN-1 by BCR-ABL suppresses autophagy in chronic myeloid leukemia
title_full_unstemmed Phosphorylation of BECLIN-1 by BCR-ABL suppresses autophagy in chronic myeloid leukemia
title_short Phosphorylation of BECLIN-1 by BCR-ABL suppresses autophagy in chronic myeloid leukemia
title_sort phosphorylation of beclin-1 by bcr-abl suppresses autophagy in chronic myeloid leukemia
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193473/
https://www.ncbi.nlm.nih.gov/pubmed/31399521
http://dx.doi.org/10.3324/haematol.2018.212027
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