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A novel AHI-1–BCR-ABL–DNM2 complex regulates leukemic properties of primitive CML cells through enhanced cellular endocytosis and ROS-mediated autophagy
- Source :
- Leukemia
- Publication Year :
- 2017
- Publisher :
- Nature Publishing Group, 2017.
-
Abstract
- Tyrosine kinase inhibitor (TKI) therapies induce clinical remission with remarkable effects on chronic myeloid leukemia (CML). However, very few TKIs completely eradicate the leukemic clone and persistence of leukemic stem cells (LSCs) remains challenging, warranting new, distinct targets for improved treatments. We demonstrated that the scaffold protein AHI-1 is highly deregulated in LSCs and interacts with multiple proteins, including Dynamin-2 (DNM2), to mediate TKI-resistance of LSCs. We have now demonstrated that the SH3 domain of AHI-1 and the proline rich domain of DNM2 are mainly responsible for this interaction. DNM2 expression was significantly increased in CML stem/progenitor cells; knockdown of DNM2 greatly impaired their survival and sensitized them to TKI treatments. Importantly, a new AHI-1-BCR-ABL-DNM2 protein complex was uncovered, which regulates leukemic properties of these cells through a unique mechanism of cellular endocytosis and ROS-mediated autophagy. Thus, targeting this complex may facilitate eradication of LSCs for curative therapies.
- Subjects :
- 0301 basic medicine
Dynamins
Cancer Research
medicine.drug_class
Clone (cell biology)
Fusion Proteins, bcr-abl
Endosomes
Biology
Endocytosis
Tyrosine-kinase inhibitor
03 medical and health sciences
Dynamin II
0302 clinical medicine
Cell Line, Tumor
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
medicine
Autophagy
Humans
RNA, Messenger
Progenitor cell
Phosphorylation
Adaptor Proteins, Signal Transducing
Myeloid leukemia
Hematology
3. Good health
Cell biology
respiratory tract diseases
Haematopoiesis
Adaptor Proteins, Vesicular Transport
030104 developmental biology
HEK293 Cells
Oncology
030220 oncology & carcinogenesis
Gene Knockdown Techniques
Original Article
Stem cell
Reactive Oxygen Species
Subjects
Details
- Language :
- English
- ISSN :
- 14765551 and 08876924
- Volume :
- 31
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Leukemia
- Accession number :
- edsair.doi.dedup.....a7f728f1c70f458ffa6bf7bdc6024bc9