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Caspase-8L expression protects CD34+ hematopoietic progenitor cells and leukemic cells from CD95-mediated apoptosis

Oncogene volume 24, pages 2421–2429 (2005)Cite this article

Abstract

Regulation of sensitivity or resistance for apoptosis by death receptor ligand systems is a key control mechanism in the hematopoietic system. Dysfunctional or deregulated apoptosis can potentially contribute to the development of immune deficiencies, autoimmune diseases, and leukemia. Control of homeostasis starts at the level of hematopoietic stem cells (HSC). To this end, we found that CD34+ hematopoietic progenitor cells are constitutively resistant to CD95-mediated apoptosis and cannot be sensitized during short-term culture to death receptor-mediated apoptosis by cytokines. Detailed analysis of the death machinery revealed that CD34+ cells do not express caspase-8a/b, a crucial constituent of the death-inducing signaling complex (DISC) of death receptors. Instead, we found a smaller splice variant termed caspase-8L to be present in HSC. Forced expression of caspase-8L using a recombinant lentiviral vector was able to protect hematopoietic cells from death receptor-induced apoptosis even in the presence of caspase-8a/b. Furthermore, we found that caspase-8L is recruited to the DISC after CD95 triggering, thereby preventing CD95 from connecting to the caspase cascade. These results demonstrate an antiapoptotic function of caspase-8L and suggest a critical role as apoptosis regulator in HSC. Similar to CD34+ HSC, stem cell-derived leukemic blasts from AML(M0) patients only expressed caspase-8L. Additionally we found, caspase-8L expression in several AML and ALL samples. Thus, caspase-8L expression might explain constitutive resistance to CD95-mediated apoptosis in CD34+ progenitor cells and might participate in the development of stem cell-derived and other leukemias by providing protection from regulatory apoptosis.

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Acknowledgements

We thank G Aggeler for excellent technical assistance. We are grateful to K Welte for providing SCF and IL-3 and thank P Krammer for supplying the cFLIP antibody NF6. This work is supported by grants from the DFG (STA 555/2-1) and European Union. The study was supported by grants from the Deutsche Forschungsgemeinschaft and Bundesministerium für Bildung und Forschung.

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  1. Klaus-Michael Debatin and Karsten Stahnke: These two authors shared senior authorship

Authors and Affiliations

  1. University Children's Hospital Ulm, University of Ulm, Prittwitzstr. 43, 89075, Ulm, Germany

    Andrea Mohr, Gergely Jarmy, Christian Beltinger, Klaus-Michael Debatin & Karsten Stahnke

  2. Division of Gene Therapy, University of Ulm, 89081, Ulm, Germany

    Ralf Michael Zwacka & Chirlei Büneker

  3. Institute of Clinical Transfusion Medicine and Immunogenetics, University of Ulm, 89081, Ulm, Germany

    Hubert Schrezenmeier & Markus Wiesneth

  4. Department of Internal Medicine III, University Hospital of Ulm, 89081, Ulm, Germany

    Konstanze Döhner

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  1. Andrea Mohr
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Correspondence to Klaus-Michael Debatin.

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Mohr, A., Zwacka, R., Jarmy, G. et al. Caspase-8L expression protects CD34+ hematopoietic progenitor cells and leukemic cells from CD95-mediated apoptosis. Oncogene 24, 2421–2429 (2005). https://doi.org/10.1038/sj.onc.1208432

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