title: Survivin isoform expression in arsenic trioxide-treated acute promyelocytic leukemia cell line and patients: The odd expression pattern of survivin-2α.
abstract: OBJECTIVE
  Survivin, an inhibitor of apoptosis protein, is overexpressed in most cancers and is associated with chemotherapy resistance, increased tumor recurrence and shorter patient survival. Several survivin splice variants have been described, and none of their expressions have been defined in acute promyelocytic leukemia (APL).
  
  
  METHODS
  Expression of the survivin gene isoforms (survivin, -2α, -2B, -ΔΕx3 and -3B) were analyzed in 50 peripheral blood and 19 bone marrow samples that were collected at different phases of the disease (diagnostic, remission and relapse) in APL patients treated with arsenic trioxide (ATO) as a front-line therapy. In addition, the human APL-derived cell line (NB4) was analyzed for the expression of survivin isoforms and capsase-3 in response to the ATO.
  
  
  RESULTS
  Survivin and its variants were overexpressed significantly in patient's bone marrow samples compared to peripheral blood or normal samples. Their expression was decreased after ATO treatment in both NB4 cells (except survivin-2α) and APL patients along with PML-RARα copy number reduction. Downregulation of survivin isoforms was associated with an increase in both caspase-3 gene expression and its enzymatic activity levels. In a patient who did not respond to ATO treatment, expression of survivin isoforms (except survivin-2α) were highly increased during the induction therapy.
  
  
  CONCLUSIONS
  Survivin isoforms are upregulated in APL patients, and their expression is diminished during the ATO treatment. In addition, overexpression of survivin and its variants (except survivin-2α) are associated with unfavorable results, suggesting that they may play an important role in mechanisms underlying the resistance of APL cells to ATO.
authors: Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.|Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors: Majid
authors: M
authors: Zaki Dizaji
authors: Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors: Seyed H
authors: SH
authors: Ghaffari
authors: Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors: Elham
authors: E
authors: Hosseini
authors: Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors: Nasrin
authors: N
authors: Alizadeh
authors: Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors: Shahrbano
authors: S
authors: Rostami
authors: Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors: Majid
authors: M
authors: Momeny
authors: Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors: Kamran
authors: K
authors: Alimoghaddam
authors: Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors: Ardeshir
authors: A
authors: Ghavamzadeh
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001853:Bone Marrow / Q000378:metabolism; D016022:Case-Control Studies; D053148:Caspase 3 / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics; D010087:Oxides / Q000494:pharmacology*; D020033:Protein Isoforms; D000077022:Survivin
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D015514:Oncogene Proteins, Fusion; D010087:Oxides; D020033:Protein Isoforms; D000077022:Survivin; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D053148:Caspase 3; D000077237:Arsenic Trioxide
keywords: acute promyelocytic leukemia; arsenic trioxide; survivin; survivin isoforms; survivin-2α