XIAP expression is post-transcriptionally upregulated in childhood ALL and is associated with glucocorticoid response in T-cell ALL.
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.


METHODS
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.


CONCLUSIONS
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.
Hundsdoerfer
Patrick
P
Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin, Berlin, Germany. patrick.hundsdoerfer@charite.de
Dietrich
Isabell
I
Schmelz
Karin
K
Eckert
Cornelia
C
Henze
Günter
G
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000473:pathology; D001856:Bone Marrow Examination; D002648:Child; D004351:Drug Resistance; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D005938:Glucocorticoids / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy; D008297:Male; D009000:Monocytes / Q000473:pathology; D010597:Pharmacogenetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D016896:Treatment Outcome; D015854:Up-Regulation; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000032:analysis / Q000235:genetics*
D005938:Glucocorticoids; D012333:RNA, Messenger; D051636:X-Linked Inhibitor of Apoptosis Protein