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Dexamethasone-induced apoptosis in acute lymphoblastic leukemia involves differential regulation of Bcl-2 family members

From the Department of Oncology and Pathology (EL, TP, KP, EB, MC, AP, DG), Institute of Environmental Medicine (BZ), Childhood Cancer Research Unit, Department of Women and Child Health, Astrid Lindgren Children’s Hospital (SS, MH), Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden, Department of Child and Adolescent Health (JM), Institute of Mother and Child, Warsaw, Poland, Divison of Hematology (EL), Internal Medicine Clinic, North Estonian Regional Hospital

Correspondence: Dan Grandér, Department of Oncology and Pathology, Cancer Centre Karolinska (CCK), Karolinska Hospital and Institute, S-171 76 Stockholm, Sweden. E-mail: dan.grander{at}ki.se

Background and Objectives: The mechanism of glucocorticoid -induced apoptosis is not fully understood and early predictive assays based on apoptotic markers for clinical outcome in acute lymphoblastic leukemia (ALL) are scarce. The aim of this study was to characterize the involvement of Bcl-2 family members and caspase activation in dexamethasone(Dex)-induced apoptosis in ALL.

Design and Methods: Primary childhood ALL samples, the pre-B ALL cell line RS(4;11), and the T-ALL cell line CCRF-CEM were used. The involvement of Bcl-2 family members was evaluated by flow cytometry, immunocytochemistry, and western and northern blotting. Apoptosis was analyzed by annexin V and TMRE staining. Caspase activity was evaluated by a fluorometric assay.

Results: Dex induced significant down-regulation of the anti-apoptotic Bcl-2 family members Bcl-2 and Bcl-xL, differential activation of the pro-apoptotic Bak and Bax, loss of m and cytochrome c release. Dex-induced apoptosis also involved early activation of caspases 2 and -3. Inhibition of caspase activity did not, however, protect against Dex-induced Bak/Bax activation, loss of m or cell death. In 12 primary ALL samples Dex-induced apoptosis was associated with activation of Bax (p=0.045) and down-regulation of Bcl-2 (p=0.016) and/or Bcl-xL (p=0.004). Furthermore, ex vivo Dex-sensitivity was associated with an early treatment response to polychemotherapy (p=0.026).

Interpretation and Conclusions: The differential regulation of pro- and anti-apoptotic Bcl-2 family members appears to be a key event in the execution of Dex-induced apoptosis in ALL cell lines, and also indicates a role for these proteins in primary ALL cells.

Key words: glucocorticoids, apoptosis, Bcl-2 family, caspases, acute lymphoblastic leukemia.