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BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition
- Source :
- Nature, vol 473, iss 7347
- Publication Year :
- 2011
- Publisher :
- eScholarship, University of California, 2011.
-
Abstract
- Tyrosine kinase inhibitors (TKIs) are widely used to treat patients with leukaemia driven by BCR-ABL1 (ref. 1) and other oncogenic tyrosine kinases. Recent efforts have focused on developing more potent TKIs that also inhibit mutant tyrosine kinases. However, even effective TKIs typically fail to eradicate leukaemia-initiating cells (LICs), which often cause recurrence of leukaemia after initially successful treatment. Here we report the discovery of a novel mechanism of drug resistance, which is based on protective feedback signalling of leukaemia cells in response to treatment with TKI. We identify BCL6 as a central component of this drug-resistance pathway and demonstrate that targeted inhibition of BCL6 leads to eradication of drug-resistant and leukaemia-initiating subclones.
- Subjects :
- Transcription, Genetic
bcr-abl
Fusion Proteins, bcr-abl
Drug Resistance
Mice, SCID
Drug resistance
Tyrosine-kinase inhibitor
Mice
0302 clinical medicine
Mice, Inbred NOD
hemic and lymphatic diseases
2.1 Biological and endogenous factors
Aetiology
Cancer
Pediatric
0303 health sciences
Multidisciplinary
breakpoint cluster region
Hematology
Precursor Cell Lymphoblastic Leukemia-Lymphoma
BCL6
3. Good health
Gene Expression Regulation, Neoplastic
DNA-Binding Proteins
5.1 Pharmaceuticals
030220 oncology & carcinogenesis
Proto-Oncogene Proteins c-bcl-6
Development of treatments and therapeutic interventions
Tyrosine kinase
Transcription
Pediatric Research Initiative
Pediatric Cancer
Childhood Leukemia
medicine.drug_class
Cell Survival
General Science & Technology
Biology
SCID
03 medical and health sciences
Rare Diseases
Genetic
Acute lymphocytic leukemia
medicine
Animals
Humans
Protein Kinase Inhibitors
030304 developmental biology
Neoplastic
Fusion Proteins
medicine.disease
Fusion protein
respiratory tract diseases
Orphan Drug
Gene Expression Regulation
Drug Resistance, Neoplasm
Cancer research
Inbred NOD
Neoplasm
ADP-Ribosylation Factor 1
Tumor Suppressor Protein p53
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Nature, vol 473, iss 7347
- Accession number :
- edsair.doi.dedup.....0b9cc6a0baeb77988d8933a4667f900e