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VEGF-induced phosphorylation of Bcl-2 influences B lineage leukemic cell response to apoptotic stimuli

Leukemia volume 19, pages 344–353 (2005)Cite this article

Abstract

Post-translational modification of Bcl-2 protein has been described in a variety of cell models with effects varying from enhanced to abrogated function. In this study, we demonstrated that Bcl-2 was constitutively phosphorylated in several hematopoietic tumor cell lines and in primary ALL cells. Increased phosphorylation of Bcl-2 protein in the JM1 ALL cell line, achieved by expression of the phosphomimetic Bcl-2 construct S70E, enhanced JM1 cell chemoresistance. In contrast, initiation of JM1 cell apoptosis was coincident with dephosphorylation of Bcl-2 and elevated protein phosphatase 2A activity. S70E expression also diminished tBid-mediated cytochrome c release and blunted chemotherapy-induced activation of caspases-9 and -3 in JM1 cells. To determine whether soluble factors produced by stromal cells in the bone marrow influence phosphorylation of Bcl-2 protein, a panel of recombinant cytokines was evaluated. Of those tested, vascular endothelial growth factor (VEGF) induced phosphorylation of Bcl-2 protein and blunted cytochrome c release during chemotherapy or tBid treatment of ALL cells. In contrast, JM1 cells transfected with S70A, resulting in expression of Bcl-2 protein that cannot be phosphorylated, were not efficiently rescued from apoptosis by VEGF. These observations suggest that optimal protection of leukemic cells by VEGF may require activation of a pathway that includes Bcl-2 phosphorylation.

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Acknowledgements

This work was supported by NIH Grant R01 HL56888 (LFG), the Dean and Charlene Hartley Leukemia Research Fund, and a WVU School of Medicine Internal Grant, Office of Research and Graduate Studies (LFG).

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Authors and Affiliations

  1. Department of Pediatrics, Robert C. Byrd Health Sciences Center, School of Medicine, West Virginia University, Morgantown, WV, USA

    L Wang, L Chen, J Fortney & L F Gibson

  2. Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, School of Medicine, West Virginia University, Morgantown, WV, USA

    J Benincosa & L F Gibson

  3. Department of Microbiology, Immunology and Cell Biology, Robert C. Byrd Health Sciences Center, School of Medicine, West Virginia University, Morgantown, WV, USA

    L F Gibson

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  1. L Wang
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Correspondence to L F Gibson.

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Wang, L., Chen, L., Benincosa, J. et al. VEGF-induced phosphorylation of Bcl-2 influences B lineage leukemic cell response to apoptotic stimuli. Leukemia 19, 344–353 (2005). https://doi.org/10.1038/sj.leu.2403643

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