Related Experiment Video
Updated: Jan 21, 2026
Flow Cytometry to Estimate Leukemia Stem Cells in Primary Acute Myeloid Leukemia and in Patient-derived-xenografts, at Diagnosis and Follow Up
Published on: March 26, 2018
Phosphorylation of BECLIN-1 by BCR-ABL suppresses autophagy in chronic myeloid leukemia
Chuanjiang Yu1, Sivahari P Gorantla1, Alina Müller-Rudorf1,2
1Department of Internal Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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.
Insights
Knocking down Beclin-1 in chronic myeloid leukemia (CML) models reduced cancer burden and improved survival. This occurs because BCR-ABL suppresses autophagy by phosphorylating Beclin-1, altering its interactions with key regulators.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Autophagy, a cellular process for adaptation to stress, plays a role in chronic myeloid leukemia (CML) treatment response.
- Limited in vivo data and incomplete understanding of autophagy regulators' mechanisms in leukemogenesis exist.
Purpose of the Study:
- Investigate the role of autophagy regulators in CML.
- Elucidate the molecular mechanism of Beclin-1 in BCR-ABL-positive cells.
Main Methods:
- Utilized a murine CML model with Beclin-1 knockdown and Atg5 deletion.
- Performed interaction analyses using phosphorylation-deficient and mimic mutants.
- Analyzed murine cell lines and primary patient material.
Main Results:
- Beclin-1 knockdown, not Atg5 deletion, reduced leukemic burden and prolonged survival in mice.
- Active BCR-ABL directly interacts with and phosphorylates Beclin-1 at Tyr233 and Tyr352, suppressing autophagy.
- BCR-ABL-induced Beclin-1 phosphorylation alters interactions with autophagy regulators (UVRAG, VPS15, ATG14, VPS34, Rubicon).
Conclusions:
- BCR-ABL directly interacts with Beclin-1, highlighting Beclin-1-mediated autophagy's importance in BCR-ABL+ cells.
- BCR-ABL-induced Beclin-1 phosphorylation is a key mechanism for regulating autophagy in CML.
- Targeting Beclin-1-mediated autophagy may offer therapeutic strategies for CML.
Related Concept Videos
01:02Phosphorylation
During phosphorylation, protein kinases transfer the terminal phosphate group of ATP to specific amino acid side chains of substrate proteins. Serine, threonine, and tyrosine are the most commonly...
01:27Autophagy
An autophagic pathway consists of a series of signaling events activated in response to diverse stress and physiological conditions such as food deprivation,...
01:15Differentiation of Common Myeloid Progenitor Cells
01:31Acid Suppressive Drugs for Peptic Ulcer Disease: Antacids
However, this neutralization reaction between...
01:23Chronic Pharyngitis
Etiology
It often arises from persistent viral or bacterial infections affecting sinuses and tonsils.
Additional contributing factors include inadequate dental hygiene, mouth breathing, recurring tonsillitis, allergic rhinitis, laryngopharyngeal reflux, and exposure to smoke, chemicals, and other environmental pollutants. Allergic reactions to pollen, mold, and pet dander, chronic cough, excessive voice usage,...
02:15SN1 Reaction: Stereochemistry
In the first step of an SN1 reaction, the bond between the electrophilic carbon and the leaving group ionizes to generate the carbocation intermediate. The second step of the mechanism is the nucleophilic attack.
In the formed carbocation, the positively charged carbon is sp2 hybridized with a trigonal planar geometry. As all the three substituents lie on the same plane, a plane of symmetry for the...