Phosphorylation of BECLIN-1 by BCR-ABL suppresses autophagy in chronic myeloid leukemia
| Autor: | Alina Müller-Rudorf, Robert Zeiser, Chuanjiang Yu, Tobias B. Huber, Lena J. Lippert, Marie Follo, Stefanie Kreutmair, Monika Engelhardt, Sivahari P. Gorantla, Anna Lena Illert, Lena Jakob, Tony Andreas Müller, Corinna Albers, Justus Duyster, Zhenyu Yue |
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| Rok vydání: | 2019 |
| Předmět: |
ATG5
Mutant Fusion Proteins bcr-abl Chronic Myeloid Leukemia UVRAG Mice 03 medical and health sciences 0302 clinical medicine Leukemia Myelogenous Chronic BCR-ABL Positive hemic and lymphatic diseases Autophagy Animals Humans Phosphorylation Tyrosine 030304 developmental biology 0303 health sciences Gene knockdown Chemistry Myeloid leukemia Articles Hematology 3. Good health Cell biology 030220 oncology & carcinogenesis Imatinib Mesylate Beclin-1 |
| Zdroj: | Haematologica |
| ISSN: | 1592-8721 0390-6078 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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