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

Oncogene volume 23, pages 4818–4827 (2004)Cite this article

Abstract

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.

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Acknowledgements

We thank Drs X Lu, K Vousden, DM Hockenbery and SJ Korsmeyer for the kind gift of reagents, and the FHCRC Proteomic Resources Center for N-terminal sequencing. This work was supported by NIH Grant RO1-CA57359 (RWC), American Cancer Society Grant RPG-97-173-01-LBC (KYJZ) and grants from Cancer Research UK and the Leukemia Research Fund.

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Author notes

  1. Kam YJ Zhang

    Present address: Plexxikon, Inc., Berkeley, CA, USA

Authors and Affiliations

  1. Cancer Sciences Division, Cancer Research UK Oncology Unit, University of Southampton School of Medicine, Southampton, UK

    Jorg Michels, Claire L Dallman, Amalia Mouzakiti, Fay Habens, Matthew Brimmell, Peter WM Johnson & Graham Packham

  2. Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Jason W O'Neill & Kam YJ Zhang

  3. Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH, USA

    Ruth W Craig

  4. Department of Molecular Pharmacology, ISIS Pharmaceuticals, Carlsbad, CA, USA

    Eric G Marcusson

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  1. Jorg Michels
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Correspondence to Graham Packham.

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Michels, J., O'Neill, J., Dallman, C. et al. Mcl-1 is required for Akata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage. Oncogene 23, 4818–4827 (2004). https://doi.org/10.1038/sj.onc.1207648

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