Back to Search
Start Over
Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival.
- Source :
-
Blood [Blood] 2012 Feb 09; Vol. 119 (6), pp. 1501-10. Date of Electronic Publication: 2011 Dec 19. - Publication Year :
- 2012
-
Abstract
- Recent evidence suggests chronic myeloid leukemia (CML) stem cells are insensitive to kinase inhibitors and responsible for minimal residual disease in treated patients. We investigated whether CML stem cells, in a transgenic mouse model of CML-like disease or derived from patients, are dependent on Bcr-Abl. In the transgenic model, after retransplantation, donor-derived CML stem cells in which Bcr-Abl expression had been induced and subsequently shut off were able to persist in vivo and reinitiate leukemia in secondary recipients on Bcr-Abl reexpression. Bcr-Abl knockdown in human CD34(+) CML cells cultured for 12 days in physiologic growth factors achieved partial inhibition of Bcr-Abl and downstream targets p-CrkL and p-STAT5, inhibition of proliferation and colony forming cells, but no reduction of input cells. The addition of dasatinib further inhibited p-CrkL and p-STAT5, yet only reduced input cells by 50%. Complete growth factor withdrawal plus dasatinib further reduced input cells to 10%; however, the surviving fraction was enriched for primitive leukemic cells capable of growth in a long-term culture-initiating cell assay and expansion on removal of dasatinib and addition of growth factors. Together, these data suggest that CML stem cell survival is Bcr-Abl kinase independent and suggest curative approaches in CML must focus on kinase-independent mechanisms of resistance.
- Subjects :
- Adaptor Proteins, Signal Transducing metabolism
Animals
Antigens, CD34 metabolism
Apoptosis drug effects
Blotting, Western
Cell Line, Tumor
Cell Proliferation drug effects
Cell Survival drug effects
Dasatinib
Dose-Response Relationship, Drug
Flow Cytometry
Fusion Proteins, bcr-abl antagonists & inhibitors
Fusion Proteins, bcr-abl genetics
Gene Expression Regulation, Leukemic
Gene Knockout Techniques
HEK293 Cells
Humans
K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology
Mice
Mice, Transgenic
Neoplastic Stem Cells pathology
Nuclear Proteins metabolism
Protein Kinase Inhibitors pharmacology
Pyrimidines pharmacology
Reverse Transcriptase Polymerase Chain Reaction
STAT5 Transcription Factor metabolism
Thiazoles pharmacology
Fusion Proteins, bcr-abl metabolism
Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism
Neoplastic Stem Cells metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 119
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 22184410
- Full Text :
- https://doi.org/10.1182/blood-2010-12-326843