title: Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia.
abstract: Relapse of drug-resistant acute lymphoblastic leukemia (ALL) has been associated with increased expression of survivin/BIRC5, an inhibitor of apoptosis protein, suggesting a survival advantage for ALL cells. In the present study, we report that inhibition of survivin in patient-derived ALL can eradicate leukemia. Targeting survivin with shRNA in combination with chemotherapy resulted in no detectable minimal residual disease in a xenograft model of primary ALL. Similarly, pharmacologic knock-down of survivin using EZN-3042, a novel locked nucleic acid antisense oligonucleotide, in combination with chemotherapy eliminated drug-resistant ALL cells. These findings show the importance of survivin expression in drug resistance and demonstrate that survivin inhibition may represent a powerful approach to overcoming drug resistance and preventing relapse in patients with ALL.
authors.affiliation: Department of Pediatrics, Division of Hematology and Oncology, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Park
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Gang
authors.forename: Yao-Te
authors.initials: YT
authors.lastname: Hsieh
authors.forename: Paul
authors.initials: P
authors.lastname: Schaefer
authors.forename: Sanna
authors.initials: S
authors.lastname: Chae
authors.forename: Lars
authors.initials: L
authors.lastname: Klemm
authors.forename: Sandra
authors.initials: S
authors.lastname: Huantes
authors.forename: Mignon
authors.initials: M
authors.lastname: Loh
authors.forename: Edward M
authors.initials: EM
authors.lastname: Conway
authors.forename: Eun-Suk
authors.initials: ES
authors.lastname: Kang
authors.forename: Hong
authors.initials: H
authors.lastname: Hoe Koo
authors.forename: Wolf-Karsten
authors.initials: WK
authors.lastname: Hofmann
authors.forename: Nora
authors.initials: N
authors.lastname: Heisterkamp
authors.forename: Louis
authors.initials: L
authors.lastname: Pelus
authors.forename: Ganesan
authors.initials: G
authors.lastname: Keerthivasan
authors.forename: John
authors.initials: J
authors.lastname: Crispino
authors.forename: Michael
authors.initials: M
authors.lastname: Kahn
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
authors.forename: Yong-Mi
authors.initials: YM
authors.lastname: Kim
mesh_terms: D000818:Animals; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015870:Gene Expression; D018390:Gene Targeting; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D018365:Neoplasm, Residual; D009841:Oligonucleotides / Q000235:genetics / Q000627:therapeutic use; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000628:therapy*; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics; D000077022:Survivin; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: C107489:BIRC5 protein, human; C117749:Birc5 protein, mouse; C552302:EZN 3042; D051034:Inhibitor of Apoptosis Proteins; D009841:Oligonucleotides; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D000077022:Survivin