Extended survival of clonal hematopoietic progenitors associated with the bcr-abl expression has a key role in the pathogenesis of Chronic Myeloid Leukemia (CML) and may concur to promote the disease progression towards the fully transformed, drug-resistant phenotype of blast crisis. Here we demonstrated that p210 bcr-abl protein tyrosine kinase (TK) activity protects bcr-abl-transducing 32D cell clones from apoptotic death through multiple pathways preserving mitochondrial membrane integrity. P210 TK prevents Trail/DR4, Bim and Bax induction and caspase 9 and Bid activation and upregulates the expression of anti-apoptotic BclxL in the cytoplasm. Moreover, it precludes the integration and aggregation of pro-apoptotic signals Bid, Bax and Bak at mitochondrial membranes letting, in turn, pore opening and apoptogenic molecule leakage from intermembrane spaces. Our results underscore the central role of Akt serine/threonine kinase, activated by p210 TK downstream of phosphatidyl-inositol 3 kinase (PI3K), in leukemic progenitor failure to undergo apoptotic death and support that pharmacological targeting of its enzymatic activity may implement the effects of TK inhibitor Imatinib mesylate (IM).

P210 BCR-ABL tyrosine kinase prevents apoptotic cell death through multiple pathways converging at mitochondrial membranes

MANCINI, MANUELA;CALONGHI, NATALIA;PAGNOTTA, ELEONORA;MASOTTI, LANFRANCO;BRUSA, GIANLUCA;ZUFFA, ELISA;SANTUCCI, MARIA ALESSANDRA
2005

Abstract

Extended survival of clonal hematopoietic progenitors associated with the bcr-abl expression has a key role in the pathogenesis of Chronic Myeloid Leukemia (CML) and may concur to promote the disease progression towards the fully transformed, drug-resistant phenotype of blast crisis. Here we demonstrated that p210 bcr-abl protein tyrosine kinase (TK) activity protects bcr-abl-transducing 32D cell clones from apoptotic death through multiple pathways preserving mitochondrial membrane integrity. P210 TK prevents Trail/DR4, Bim and Bax induction and caspase 9 and Bid activation and upregulates the expression of anti-apoptotic BclxL in the cytoplasm. Moreover, it precludes the integration and aggregation of pro-apoptotic signals Bid, Bax and Bak at mitochondrial membranes letting, in turn, pore opening and apoptogenic molecule leakage from intermembrane spaces. Our results underscore the central role of Akt serine/threonine kinase, activated by p210 TK downstream of phosphatidyl-inositol 3 kinase (PI3K), in leukemic progenitor failure to undergo apoptotic death and support that pharmacological targeting of its enzymatic activity may implement the effects of TK inhibitor Imatinib mesylate (IM).
M. Mancini; N. Calonghi; E. Pagnotta; L. Masotti; G. Brusa; E. Zuffa; A. Calabrò; E. Barbieri; M. A. Santucci
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/22758
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