Page 125 - Haematologica May 2020

Chronic Myeloid Leukemia
Phosphorylation of BECLIN-1 by BCR-ABL suppresses autophagy in chronic myeloid leukemia
Ferrata Storti Foundation
Haematologica 2020 Volume 105(5):1285-1293
Chuanjiang Yu,1 Sivahari P. Gorantla,1 Alina Müller-Rudorf,1,2 Tony A. Müller,1 Stefanie Kreutmair,1 Corinna Albers,3 Lena Jakob,1 Lena J. Lippert,1
Zhenyu Yue,4 Monika Engelhardt,1 Marie Follo,1 Robert Zeiser,1,2
Tobias B. Huber,5,6,7 Justus Duyster1,2 and Anna L. Illert1,2
1Department of Internal Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; 2German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany; 3Department of Medicine, Klinikum rechts der Isar, Technical University München, München, Germany; 4Department of Neurology and Neuroscience, Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY, USA; 5Department of Medicine, University Medical Center Hamburg- Eppendorf, Hamburg, Germany; 6Department of Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany and 7BIOSS Center for Biological Signalling Studies and Center for Systems Biology (ZBSA), Albert-Ludwigs-University, Freiburg, Germany
ABSTRACT
Autophagy is a genetically regulated process of adaptation to metabol- ic 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.
Introduction
The BCR-ABL fusion kinase has been identified in more than 95% of chronic myeloid leukemia (CML) and 20% of acute lymphoblastic leukemia (ALL) cases.1,2 Oncogenic BCR-ABL activates several aberrant kinase-dependent pathways includ- ing anti-apoptosis, proliferation and differentiation,3,4 leading to the development of several successful tyrosine kinase inhibitors (TKI) in BCR-ABL+ leukemia treatment.5,6 However, there are still unsolved issues in TKI-based therapies for patients with CML: Suppression of the disease relies in most patients on continuous and lifelong TKI therapy7,8 and disease relapse occurs due to emerged TKI resistance.9-11 Thus, identification of additional important mediators could significantly improve CML therapy.
Autophagy is an evolutionarily conserved mechanism for the degradation of cyto- plasmic components including organelles and proteins and plays an important role in cellular homeostasis. Because of its potential role in metabolism and cell survival, altered autophagy processes are critical for cancer cell fate. Several reports indicate
Correspondence:
ANNA LENA ILLERT
lena.illert@uniklinik-freiburg.de
Received: January 18, 2019. Accepted: August 7, 2019. Pre-published: August 8, 2019.
doi:10.3324/haematol.2018.212027
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/5/1285
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