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Increased caspase-3 activity in refractory anemias: lack of evidence for Fas pathway implication

Leukemia volume 16, pages 2343–2345 (2002)Cite this article

The myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis, peripheral blood cytopenias and abnormal growth of marrow committed progenitor cells. In line with the apparent contradiction between a frequently increased marrow cellularity and peripheral cytopenias, it has been hypothesized that the functional bone marrow failure is due to premature intramedullary cell death by apoptosis. We recently described an increased activation of cysteine proteases (caspases), particularly the major effector protein of the programmed cell death caspase-3, which was readily inhibited by a specific caspase inhibitor Ac-DEVD-CHO. This was especially observed in refractory anemia (RA) and RA with ringed sideroblasts (RARS),1 Others studies have shown that MDS bone marrow mononuclear cells or CD34+ cells strongly expressed Fas and Fas-L as compared to cells of normal individuals.2,3 Signaling through Fas requires the formation of a death-inducing signaling complex (DISC) that involves the cytoplasmic domain of Fas, the adaptor molecule FADD/MORT-1, and procaspase-8. Activated caspase-8 subsequently cleaves caspase-3 either directly or through the activation of Bid, a pro-apoptotic member of the Bcl-2 family which in turn releases mitochondrial cytochrome-c.4

The present study investigated the functional role of the Fas/Fas-L pathway in the increased apoptosis of hematopoietic cells in a series of nine RA and three RARS samples according to the FAB classification (Table 1). We assessed caspase-3 and -8 activities and Bid expression in bone marrow mononuclear cells (BMMNC) immediately after separation (T0) and/or after 24 h culture (T24h) in RPMI medium supplemented with 10% of fetal calf serum. In some experiments (five RA samples) Fas receptor was blocked by addition of an antagonistic anti-Fas antibody (clone ZB4, 500 ng/ml) into the culture.

Table 1 Clinical characteristics of patients
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Acknowledgements

Work supported by a grant from Comité Départemental de la Lutte contre le Cancer de la Loire.

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Authors and Affiliations

  1. Equipe ‘Mort Cellulaire et Néoplasies’, Faculté de Médecine, Saint-Etienne, France

    D Boudard, S Piselli, D Guyotat & L Campos

  2. Unité INSERM U517, Faculté de Médecine et Pharmacie, Dijon, France

    O Sordet

  3. Département d'Hématologie, CHU de Saint-Etienne, France

    A Viallet, D Guyotat & L Campos

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  1. D Boudard
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Boudard, D., Sordet, O., Piselli, S. et al. Increased caspase-3 activity in refractory anemias: lack of evidence for Fas pathway implication. Leukemia 16, 2343–2345 (2002). https://doi.org/10.1038/sj.leu.2402700

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