Background: Resistance to glucocorticoid induced apoptosis is one of the major risk factors for relapse and poor outcome in childhood acute lymphoblastic leukemia (ALL). Overexpression of X-linked inhibitor of apoptosis protein (XIAP) has been shown to be associated with chemotherapy resistance in several malignancies.
Procedure: XIAP protein and mRNA expression were determined in leukemic blasts of 51 childhood ALL patients and normal bone marrow mononuclear cells. XIAP expression was correlated with glucocorticoid response and outcome.
Results: XIAP protein but not mRNA expression was found to be highly increased in childhood ALL compared to control bone marrow mononuclear cells (MNC) (median: 3.5 vs. 0.14 ng/10(5) MNC, P < 0.0001) indicating a post-transcriptional regulation of XIAP expression. In patients with T-cell ALL, poor prednisone response was associated with increased XIAP expression (median: 2.8 in good vs. 5.8 in poor responders; P = 0.005). Similarly, T-cell ALL patients suffering adverse events showed higher initial XIAP levels than patients in continuous complete remission (CCR) (median: 2.7 in patients in CCR vs. 5.6 in patients suffering adverse events; P = 0.007). XIAP inhibition using the low-molecular-weight SMAC mimetic LBW242 resulted in a significant increase of prednisone-induced apoptosis in vitro.
Conclusion: In childhood ALL compared to control bone marrow, the expression of the apoptosis inhibitor XIAP is highly increased by post-transcriptional regulation. The association with poor in vivo glucocorticoid response and outcome in T-cell ALL suggests XIAP inhibition as a promising novel approach for the treatment of resistant ALL.
(c) 2010 Wiley-Liss, Inc.