title: A subset of chronic lymphocytic leukemia patients display reduced levels of PARP1 expression coupled with a defective irradiation-induced apoptosis.
abstract: Chronic lymphocytic leukemia (CLL) is a heterogeneous disease characterized by defects in the DNA damage response and apoptosis. Among the factors involved in these pathways, we focused on the enzyme poly(ADP-ribose) polymerase 1 (PARP1) and on its substrate Che-1 by evaluating their basal expression and functional changes upon irradiation (IR). Microarray experiments were performed on 98 untreated CLL cases. Next, freshly isolated primary cells from 21 untreated patients were analyzed for in vitro response to irradiation through Western blot, PARP activity assay, Annexin-V analysis, and PARP1 basal expression by quantitative polymerase chain reaction. Microarray analysis showed that PARP1 and CHE1 were constitutively expressed in CLL and had a high degree of correlation with each other and with TP53. PARP1 and TP53 downmodulation was associated with worse clinical outcomes, especially in TP53-mutated cases. Next, CLL samples from 21 untreated patients were classified as responders and nonresponders based on IR-induced PARP1 cleavage. Notably, while responder samples were characterized by Che-1 and p53 induction at 8 hours and reduction at 24 hours post-IR, nonresponders included both samples with p53 dysfunctions and cases with a normal IR-induced Che-1 and/or p53 response. Finally, we observed that PARP1 was downregulated in nonresponder vs responder samples and that its basal expression was positively correlated with PARP1 cleavage after IR. In conclusion, we showed that reduced expression of PARP1 is associated with an impairment of CLL responsiveness to cell death.
authors: Section of Clinical Biochemistry, Department of Cellular Biotechnologies and Hematology, "Sapienza" University of Rome, Italy.
authors: Maria Giulia
authors: MG
authors: Bacalini
authors: Simona
authors: S
authors: Tavolaro
authors: Nadia
authors: N
authors: Peragine
authors: Marilisa
authors: M
authors: Marinelli
authors: Simona
authors: S
authors: Santangelo
authors: Ilaria
authors: I
authors: Del Giudice
authors: Francesca Romana
authors: FR
authors: Mauro
authors: Valeria
authors: V
authors: Di Maio
authors: Maria Rosaria
authors: MR
authors: Ricciardi
authors: Paola
authors: P
authors: Caiafa
authors: Sabina
authors: S
authors: Chiaretti
authors: Robin
authors: R
authors: Foà
authors: Anna
authors: A
authors: Guarini
authors: Anna
authors: A
authors: Reale
mesh_terms: D017209:Apoptosis / Q000528:radiation effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000528:radiation effects; D005720:Gamma Rays; D015973:Gene Expression Regulation, Leukemic / Q000528:radiation effects*; D016158:Genes, p53; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: C402637:AATF protein, human; D051017:Apoptosis Regulatory Proteins; D004273:DNA, Neoplasm; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases