Mcl-1 is required for Akata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage

• Published in: Oncogene Vol. 23; no. 28; pp. 4818 - 4827
• Main Authors: MICHELS, Jorg, O'NEILL, Jason W, PACKHAM, Graham, DALLMAN, Claire L, MOUZAKITI, Amalia, HABENS, Fay, BRIMMELL, Matthew, ZHANG, Kam Y. J, CRAIG, Ruth W, MARCUSSON, Eric G, JOHNSON, Peter W. M
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 17.06.2004; Nature Publishing Group
• Subjects: Ageing, cell death; Antisense oligonucleotides; Apoptosis; Apoptosis - physiology; Aspartic acid; Bcl-2 protein; Bcl-x protein; Biological and medical sciences; Biopsy; Cancer research; Caspase; Caspases - metabolism; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Death; Cell Line, Tumor; Cell physiology; Cell survival; Cell Survival - physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cisplatin; Fundamental and applied biological sciences. Psychology; Hematologic and hematopoietic diseases; Humans; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphatic system; Lymphocytes B; Lymphoma; Lymphoma, B-Cell - pathology; Mcl-1 protein; Medical research; Medical sciences; Molecular and cellular biology; Oligodeoxyribonucleotides, Antisense - pharmacology; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Oncology; Open Reading Frames; Plasmids; Proteins; Thionucleotides - pharmacology; Transfection; Tumor cell lines; United Kingdom > UK; United States > US; Bcl-2; Enzyme; Caspase; Malignant hemopathy; Non Hodgkin lymphoma; Carcinogenesis; Survival; Peptidases; Mcl-1; Cell death; non-Hodgkin's lymphoma; Lymphoproliferative syndrome; C-Onc gene; Hydrolases; Protooncogene; Apoptosis; antisense
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1207648

Enforced expression of the antiapoptotic Bcl-2 family protein Mcl-1 promotes lymphomagenesis in the mouse; however, the functional role of Mcl-1 in human B-cell lymphoma remains unclear. We demonstrate that Mcl-1 is widely expressed in malignant B-cells, and high-level expression of Mcl-1 is required for B-lymphoma cell survival, since transfection of Mcl-1-specific antisense oligodeoxynucleotides was sufficient to promote apoptosis in Akata6 lymphoma cells. Mcl-1 was efficiently cleaved by caspases at evolutionarily conserved aspartic acid residues in vitro, and during cisplatin-induced apoptosis in B-lymphoma cell lines and spontaneous apoptosis of primary malignant B-cells. Overexpression of the Mcl-1 cleavage product that accumulated during apoptosis was sufficient to kill cells. Therefore, Mcl-1 is an essential survival molecule for B-lymphoma cells and is cleaved by caspases to a death-promoting molecule during apoptosis. In contrast to Mcl-1, Bcl-2 and Bcl-XL were relatively resistant to caspase cleavage in vitro and in intact cells. Interfering with Mcl-1 function appears to be an effective means of inducing apoptosis in Mcl-1-positive B-cell lymphoma, and the unique sensitivity of Mcl-1 to caspase-mediated cleavage suggests an attractive strategy for converting it to a proapoptotic molecule.