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Br J Haematol. 2014 Oct;167(1):87-99. doi: 10.1111/bjh.13011. Epub 2014 Jul 4.

Wnt inhibition leads to improved chemosensitivity in paediatric acute lymphoblastic leukaemia.

Author information

NYU Cancer Institute, NYU Langone Medical Center, New York, NY.
Department of Pediatrics, Staten Island University Hospital.
Department of Pediatrics, University of California School of Medicine, San Francisco, California.
NYU School of Medicine.
University of Colorado School of Medicine, Aurora, Colorado.
Department of Biochemistry and Molecular Pharmacology, NYU Langone Medical Center, New York, NY.
Department of Pathology, NYU Langone Medical Center, New York, NY.
Contributed equally


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.


Wnt inhibition; acute lymphoblastic leukaemia; chemosensitivity; phosphoflow cytometry; relapse

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