Optimized induction of mitochondrial apoptosis for chemotherapy-free treatment of BCR-ABL+acute lymphoblastic leukemia.
Leukemia
; 33(6): 1313-1323, 2019 06.
Article
in En
| MEDLINE
| ID: mdl-30546081
ABSTRACT
BCR-ABL+acute lymphoblastic leukemia (ALL) in adults has a poor prognosis with allogeneic stem cell transplantation (SCT) considered the best curative option for suitable patients. We here characterize the curative potential of BH3-mimetics differentially targeting mitochondrial BCL2-family members using a combination therapy approach with dexamethasone and tyrosine kinase inhibitors targeting BCR-ABL. In BCR-ABL + ALL BH3-mimetics act by redistribution of mitochondrial activator BIM, which is strongly required for cytotoxicity of the BCL2-specific BH3-mimetic ABT-199, tyrosine kinase inhibitors (TKIs) and dexamethasone. BIM expression is enhanced by dexamethasone and TKIs and both synergize with ABT-199 in BCR-ABL + ALL. Triple combinations with ABT-199, dexamethasone and TKIs efficiently attenuate leukemia progression both in tissue culture and in primary cell xenotransplantation models. Notably, the dasatinib-containing combination led to treatment- and leukemia-free long-term survival in a BCR-ABL + mouse model. Finally, response to BH3-mimetics can be predicted for individual patients in a clinically relevant setting. These data demonstrate curative targeted and chemotherapy-free pharmacotherapy for BCR-ABL + ALL in a preclinical model. Clinical evaluation, in particular for patients not suitable for allogeneic SCT, is warranted.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
/
Antineoplastic Combined Chemotherapy Protocols
/
Apoptosis
/
Mitochondria
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Leukemia
Journal subject:
HEMATOLOGIA
/
NEOPLASIAS
Year:
2019
Document type:
Article
Affiliation country: