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Ehrhardt, H. ; Wachter, F. ; Maurer, M. ; Stahnke, K.* ; Jeremias, I.

Important role of Caspase-8 for chemo-sensitivity of ALL cells.

Clin. Cancer Res. 17, 7605-7613 (2011)

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PURPOSE: Sensitivity of tumor cells towards chemotherapy mainly determines the prognosis of patients suffering from acute lymphoblastic leukemia (ALL); nevertheless, underlying mechanisms regulating chemo-sensitivity remain poorly understood. Here, we aimed at characterizing the role of Caspase-8 for chemo-sensitivity of B- and T-ALL cells. EXPERIMENTAL DESIGN: Primary tumor cells from children with ALL were evaluated for expression levels of the Caspase-8 protein, were amplified in NSG-mice, transfected with siRNA and evaluated for their chemo-sensitivity in vitro. RESULTS: Effective cell death in B- and T-ALL cells depended on the presence of Caspase-8 for the majority of cytotoxic drugs routinely used in anti-leukemia treatment. Caspase-8 was activated independently from extrinsic apoptosis signaling. Accordingly in primary ALL cells, the expression level of Caspase-8 protein correlated with cell death sensitivity towards defined cytotoxic drugs in vitro. In the subgroup of primary ALL cells with low expression of Caspase-8, methotrexate upregulated the expression of Caspase-8 mediated by the transcription factor p53 suggesting epigenetic silencing of Caspase-8. RNA interference in patient-derived B- and T-ALL cells revealed that effective cell death induction by most routine drug combinations involving methotrexate depended on the presence of Caspase-8. CONCLUSION: Our results indicate that Caspase-8 is crucial for the high anti-leukemic efficiency of numerous routine cytotoxic drugs. Re-expression of epigenetically downregulated Caspase-8 represents a promising approach to increase efficiency of anti-leukemic therapy.

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