title: M4 and M5 acute myeloid leukaemias display a high sensitivity to Bortezomib-mediated apoptosis.
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-1beta-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.
authors: Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors: Roberta
authors: R
authors: Riccioni
authors: Mara
authors: M
authors: Senese
authors: Daniela
authors: D
authors: Diverio
authors: Viviana
authors: V
authors: Riti
authors: Sonia
authors: S
authors: Buffolino
authors: Gualtiero
authors: G
authors: Mariani
authors: Alessandra
authors: A
authors: Boe
authors: Michele
authors: M
authors: Cedrone
authors: Francesco
authors: F
authors: Lo-Coco
authors: Robin
authors: R
authors: Foà
authors: Cesare
authors: C
authors: Peschle
authors: Ugo
authors: U
authors: Testa
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D017209:Apoptosis; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000032:analysis / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002478:Cells, Cultured; D053200:Fas-Associated Death Domain Protein / Q000032:analysis / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D007948:Leukemia, Monocytic, Acute / Q000188:drug therapy* / Q000473:pathology; D015479:Leukemia, Myelomonocytic, Acute / Q000188:drug therapy* / Q000473:pathology; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011719:Pyrazines / Q000627:therapeutic use*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000032:analysis; D013234:Stem Cells / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000032:analysis; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000032:analysis / Q000378:metabolism
chemical_list: D001897:Boronic Acids; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D011480:Protease Inhibitors; D011719:Pyrazines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D000069286:Bortezomib; D000444:Aldehyde Dehydrogenase; D053148:Caspase 3; D053181:Caspase 8