title: Decreased PARP and procaspase-2 protein levels are associated with cellular drug resistance in childhood acute lymphoblastic leukemia.
abstract: 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 poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) in cells from children with acute lymphoblastic leukemia (ALL; n = 43) and acute myeloid leukemia (AML; n = 10). PARP expression was present in all B-lineage samples, but absent in 4 of 15 T-lineage ALL samples and 3 of 10 AML cases, which was not caused by genomic deletions. PARP expression was a median 7-fold lower in T-lineage ALL (P < .001) and 10-fold lower in AML (P < .001) compared with B-lineage ALL. PARP expression was 4-fold lower in prednisolone, vincristine and L-asparaginase (PVA)-resistant compared with PVA-sensitive ALL patients (P < .001). Procaspase-2 expression was 3-fold lower in T-lineage ALL (P = .022) and AML (P = .014) compared with B-lineage ALL. In addition, procaspase-2 expression was 2-fold lower in PVA-resistant compared to PVA-sensitive ALL patients (P = .042). No relation between apoptotic protease-activating factor 1 (Apaf-1), procaspases-3, -6, -7, -8, -10, and drug resistance was found. In conclusion, low baseline expression of PARP and procaspase-2 is related to cellular drug resistance in childhood acute lymphoblastic leukemia.
authors.affiliation: Erasmus MC/Sophia Children's Hospital, Pediatric Oncology/Hematology, Dr. Molewaterplein 60, 3015 GJ Rotterdam, The Netherlands.
authors.forename: Amy
authors.initials: A
authors.lastname: Holleman
authors.forename: Monique L
authors.initials: ML
authors.lastname: den Boer
authors.forename: Karin M
authors.initials: KM
authors.lastname: Kazemier
authors.forename: H Berna
authors.initials: HB
authors.lastname: Beverloo
authors.forename: Anne R M
authors.initials: AR
authors.lastname: von Bergh
authors.forename: Gritta E
authors.initials: GE
authors.lastname: Janka-Schaub
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
mesh_terms: D017209:Apoptosis / Q000502:physiology; D053143:Caspase 2; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002648:Child; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004354:Drug Screening Assays, Antitumor; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000502:physiology
chemical_list: D012333:RNA, Messenger; D011065:Poly(ADP-ribose) Polymerases; D053143:Caspase 2; D020169:Caspases