title: Wnt inhibition leads to improved chemosensitivity in paediatric acute lymphoblastic leukaemia.
abstract: While childhood acute lymphoblastic leukaemia (ALL) is now highly curable, the dismal prognosis for children who relapse warrants novel therapeutic approaches. Previously, using an integrated genomic analysis of matched diagnosis-relapse paired samples, we identified overactivation of the Wnt pathway as a possible mechanism of recurrence. To validate these findings and document whether Wnt inhibition may sensitize cells to chemotherapy, we analysed the expression of activated β-catenin (and its downstream target BIRC5) using multiparameter phosphoflow cytometry and tested the efficacy of a recently developed Wnt inhibitor, iCRT14, in ALL cell lines and patient samples. We observed increased activation of β-catenin at relapse in 6/10 patients. Furthermore, treatment of leukaemic cell lines with iCRT14 led to significant downregulation of Wnt target genes and combination with traditional chemotherapeutic drugs resulted in a synergistic decrease in viability as well as a significant increase in apoptotic cell death. Finally, pre-treatment of purified blasts from patients with relapsed leukaemia with the Wnt inhibitor followed by exposure to prednisolone, restored chemosensitivity in these cells. Our results demonstrate that overactivation of the Wnt pathway may contribute to chemoresistance in relapsed childhood ALL and that Wnt-inhibition may be a promising therapeutic approach.
authors.affiliation: NYU Cancer Institute, NYU Langone Medical Center, New York, NY.
authors.forename: Smita
authors.initials: S
authors.lastname: Dandekar
authors.affiliation: NYU Cancer Institute, NYU Langone Medical Center, New York, NY.|Department of Pediatrics, Staten Island University Hospital.
authors.forename: Eleny
authors.initials: E
authors.lastname: Romanos-Sirakis
authors.affiliation: Department of Pediatrics, University of California School of Medicine, San Francisco, California.
authors.forename: Faye
authors.initials: F
authors.lastname: Pais
authors.affiliation: NYU Cancer Institute, NYU Langone Medical Center, New York, NY.
authors.forename: Teena
authors.initials: T
authors.lastname: Bhatla
authors.affiliation: NYU Cancer Institute, NYU Langone Medical Center, New York, NY.
authors.forename: Courtney
authors.initials: C
authors.lastname: Jones
authors.affiliation: NYU School of Medicine.
authors.forename: Wallace
authors.initials: W
authors.lastname: Bourgeois
authors.affiliation: University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.affiliation: NYU Cancer Institute, NYU Langone Medical Center, New York, NY.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Raetz
authors.affiliation: Department of Pediatrics, University of California School of Medicine, San Francisco, California.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Hermiston
authors.affiliation: NYU Cancer Institute, NYU Langone Medical Center, New York, NY.|Department of Biochemistry and Molecular Pharmacology, NYU Langone Medical Center, New York, NY.
authors.forename: Ramanuj
authors.initials: R
authors.lastname: Dasgupta
authors.affiliation: NYU Cancer Institute, NYU Langone Medical Center, New York, NY.
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Morrison
authors.affiliation: NYU Cancer Institute, NYU Langone Medical Center, New York, NY.|Department of Pathology, NYU Langone Medical Center, New York, NY.
authors.forename: William L
authors.initials: WL
authors.lastname: Carroll
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016130:Immunophenotyping; D009364:Neoplasm Recurrence, Local; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D051153:Wnt Proteins
keywords: Wnt inhibition; acute lymphoblastic leukaemia; chemosensitivity; phosphoflow cytometry; relapse