title: Targeting survivin and p53 in pediatric acute lymphoblastic leukemia.
abstract: Despite advances in treatment and outcomes for patients with pediatric acute lymphoblastic leukemia (ALL), there continue to be subsets of patients who are refractory to standard chemotherapy and hematopoietic stem cell transplant. Therefore, novel gene targets for therapy are needed to further advance treatment for this disease. RNA interference technology has identified survivin as a potential therapeutic target. Survivin, a member of the inhibitor of apoptosis (IAP) proteins and chromosome passenger complex, is expressed in hematologic malignancies and overexpressed in relapsed pediatric ALL. Our studies show that survivin is uniformly expressed at high levels in multiple pediatric ALL cell lines. Furthermore, silencing of survivin expression in pediatric ALL cell lines as well as primary leukemic blasts reduces viability of these cells. This includes cell lines derived from patients with relapsed disease featuring cytogenetic anomalies such as t(12;21), Philadelphia chromosome t(9;22), t(1;19) as well as a cell line carrying t(17;19) from a patient with de novo ALL. Furthermore, inhibition of survivin increases p53-dependent apoptosis that can be rescued by inhibition of p53. Finally, a screen of randomly selected primary patient samples confirms that survivin-specific small interfering RNA and survivin-targeted drug, YM155, effectively reduce viability of leukemic blasts.
authors.affiliation: Division of Hematology and Medical Oncology, and OHSU Knight Cancer Institute, OHSU, Portland, OR, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Tyner
authors.forename: A M
authors.initials: AM
authors.lastname: Jemal
authors.forename: M
authors.initials: M
authors.lastname: Thayer
authors.forename: B J
authors.initials: BJ
authors.lastname: Druker
authors.forename: B H
authors.initials: BH
authors.lastname: Chang
mesh_terms: D017209:Apoptosis; D001549:Benzamides; D002455:Cell Division; D045744:Cell Line, Tumor; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors; D016195:G2 Phase; D006801:Humans; D000068877:Imatinib Mesylate; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000627:therapeutic use; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011743:Pyrimidines / Q000627:therapeutic use; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
chemical_list: C107489:BIRC5 protein, human; D001549:Benzamides; D051034:Inhibitor of Apoptosis Proteins; D010879:Piperazines; D011743:Pyrimidines; D000077022:Survivin; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl