The present study explored the sensitivity of leukaemic blasts derived from 30 acute myeloid leukaemia (AML) patients to Bortezomib. Bortezomib induced apoptosis of primary AML blasts: 18/30 AMLs were clearly sensitive to the proapoptotic effects of Bortezomib, while the remaining cases were moderately sensitive to this molecule. The addition of tumour necrosis factor-related-apoptosis-inducing ligand, when used alone, did not induce apoptosis of AML blasts and further potentiated the cytotoxic effects of Bortezomib. The majority of AMLs sensitive to Bortezomib showed immunophenotypic features of the M4 and M5 French-American-British classification subtypes and displayed myelomonocytic features. All AMLs with mutated FLT3 were in the Bortezomib-sensitive group. Biochemical studies showed that: (i) Bortezomib activated caspase-8 and caspase-3 and decreased cellular FLICE [Fas-associated death domain (FADD)-like interleukin-1 beta-converting enzyme]-inhibitory protein (c-FLIP) levels in AML blasts; (ii) high c-FLIP levels in AML blasts were associated with low Bortezomib sensitivity. Finally, analysis of the effects of Bortezomib on leukaemic cells displaying high aldehyde dehydrogenase activity suggested that this drug induced in vitro killing of leukaemic stem cells. The findings of the present study, further support the development of Bortezomib as an anti-leukaemic drug and provide simple tools to predict the sensitivity of AML cells to this drug.

Riccioni, R., Senese, M., Diverio, D., Riti, V., Buffolino, S., Mariani, G., et al. (2007). M4 and M5 acute myeloid leukaemias display a high sensitivity to Bortezomib-mediated apoptosis. BRITISH JOURNAL OF HAEMATOLOGY, 139(2), 194-205 [10.1111/j.1365-2141.2007.06757.x].

M4 and M5 acute myeloid leukaemias display a high sensitivity to Bortezomib-mediated apoptosis

LO COCO, FRANCESCO;
2007-01-01

Abstract

The present study explored the sensitivity of leukaemic blasts derived from 30 acute myeloid leukaemia (AML) patients to Bortezomib. Bortezomib induced apoptosis of primary AML blasts: 18/30 AMLs were clearly sensitive to the proapoptotic effects of Bortezomib, while the remaining cases were moderately sensitive to this molecule. The addition of tumour necrosis factor-related-apoptosis-inducing ligand, when used alone, did not induce apoptosis of AML blasts and further potentiated the cytotoxic effects of Bortezomib. The majority of AMLs sensitive to Bortezomib showed immunophenotypic features of the M4 and M5 French-American-British classification subtypes and displayed myelomonocytic features. All AMLs with mutated FLT3 were in the Bortezomib-sensitive group. Biochemical studies showed that: (i) Bortezomib activated caspase-8 and caspase-3 and decreased cellular FLICE [Fas-associated death domain (FADD)-like interleukin-1 beta-converting enzyme]-inhibitory protein (c-FLIP) levels in AML blasts; (ii) high c-FLIP levels in AML blasts were associated with low Bortezomib sensitivity. Finally, analysis of the effects of Bortezomib on leukaemic cells displaying high aldehyde dehydrogenase activity suggested that this drug induced in vitro killing of leukaemic stem cells. The findings of the present study, further support the development of Bortezomib as an anti-leukaemic drug and provide simple tools to predict the sensitivity of AML cells to this drug.
2007
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/15 - MALATTIE DEL SANGUE
English
Con Impact Factor ISI
apoptosis; leukaemia; proteasome; aldehyde dehydrogenase; bortezomib; caspase 3; caspase 8; tumor necrosis factor; acute granulocytic leukemia; article; cell killing; chemical analysis; clinical article; drug effect; drug mechanism; drug sensitivity; enzyme activation; gene mutation; human; human cell; immunophenotyping; in vitro study; priority journal; stem cell; aldehyde dehydrogenase; boronic acids; CASP8 and FADD-like apoptosis regulating protein; cells, cultured; fas-associated death domain protein; flow cytometry; immunophenotyping; leukemia, myelomonocytic, acute; protease inhibitors; pyrazines; receptors, TNF-related apoptosis-inducing ligand
Riccioni, R., Senese, M., Diverio, D., Riti, V., Buffolino, S., Mariani, G., et al. (2007). M4 and M5 acute myeloid leukaemias display a high sensitivity to Bortezomib-mediated apoptosis. BRITISH JOURNAL OF HAEMATOLOGY, 139(2), 194-205 [10.1111/j.1365-2141.2007.06757.x].
Riccioni, R; Senese, M; Diverio, D; Riti, V; Buffolino, S; Mariani, G; Boe, A; Cedrone, M; LO COCO, F; Foa, R; Peschle, C; Testa, U
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/8130
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