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Blood, 1 September 2005, Vol. 106, No. 5, pp. 1817-1823.
Prepublished online as a Blood First Edition Paper on May 17, 2005; DOI 10.1182/blood-2004-11-4296.
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Submitted November 10, 2004
Accepted May 6, 2005
Decreased PARP and procaspase-2 protein levels are associated with cellular drug resistance in childhood acute lymphoblastic leukemia
Amy Holleman, Monique L den Boer*, Karin M Kazemier, H B Beverloo, Anne R von Bergh, Gritta E Janka-Schaub, and Rob Pieters
Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands
Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands; Department of Clinical Genetics, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands
Department of Clinical Genetics, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands
Cooperative Acute Lymphoblastic Leukemia (COALL) study group/ Children's University Hospital, Hamburg, Germany
* Corresponding author; email: m.l.denboer{at}erasmusmc.nl.
Drug resistance in childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) is associated with impaired ability to induce apoptosis. To elucidate causes of apoptotic defects, we studied the protein expression of Apaf-1, procaspases-2, -3, -6, -7, -8, -10, and PARP in cells from children with ALL (n=43) and AML (n=10). PARP expression was present in all B-lineage samples, but absent in 4/15 T-ALL and 3/10 AML cases, which was not caused by genomic deletions. PARP expression was median 7-fold lower in T-lineage ALL (P< 0.001) and 10-fold lower in AML (P< 0.001) compared to B-lineage ALL. PARP expression was 4-fold lower in prednisolone, vincristine and L-asparaginase (PVA) resistant compared to PVA sensitive ALL patients (P< 0.001). Procaspase-2 expression was 3-fold lower in T-lineage ALL (P=0.022) and AML (P=0.014) compared to B-lineage ALL. In addition, procaspase-2 expression was 2-fold lower in PVA resistant compared to PVA sensitive ALL patients (P=0.042). No relation between Apaf-1, procaspase-3, -6, -7, -8, -10 and drug resistance was found. In conclusion, low base-line expression of PARP and procaspase-2 is related to cellular drug resistance in childhood acute lymphoblastic leukemia.
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