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

Abstract

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.

• Authors: Chuanjiang Yu, Sivahari P Gorantla, Alina Müller-Rudorf, Tony A Müller, Stefanie Kreutmair, Corinna Albers, Lena Jakob, Lena J Lippert, Zhenyu Yue, Monika Engelhardt, Marie Follo, Robert Zeiser, Tobias B Huber, Justus Duyster, Anna L Illert
• Journal: Haematologica (Haematologica) Vol. 105 Issue 5 Pg. 1285-1293 (05 2020) ISSN: 1592-8721 [Electronic] Italy
• PMID: 31399521 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© 2020 Ferrata Storti Foundation.

Chemical References

• Beclin-1
• Imatinib Mesylate
• Fusion Proteins, bcr-abl

Topics

• Animals
• Autophagy
• Beclin-1 (genetics)
• Fusion Proteins, bcr-abl (genetics, metabolism)
• Humans
• Imatinib Mesylate (pharmacology)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (genetics)
• Mice
• Phosphorylation