Wnt inhibition leads to improved chemosensitivity in paediatric acute lymphoblastic leukaemia

Smita Dandekar, Eleny Romanos-Sirakis, Faye Pais, Teena Bhatla, Courtney Jones, Wallace Bourgeois, Stephen P. Hunger, Elizabeth A. Raetz, Michelle L. Hermiston, Ramanuj Dasgupta, Debra J. Morrison, William L. Carroll

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Summary: 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.

Original languageEnglish (US)
Pages (from-to)87-99
Number of pages13
JournalBritish Journal of Haematology
Volume167
Issue number1
DOIs
StatePublished - Oct 1 2014

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Pediatrics
Recurrence
Catenins
Wnt Signaling Pathway
Cell Line
Therapeutics
Prednisolone
Leukemia
Cell Death
Down-Regulation
Drug Therapy
Pharmaceutical Preparations
Genes

All Science Journal Classification (ASJC) codes

  • Hematology

Cite this

Dandekar, S., Romanos-Sirakis, E., Pais, F., Bhatla, T., Jones, C., Bourgeois, W., ... Carroll, W. L. (2014). Wnt inhibition leads to improved chemosensitivity in paediatric acute lymphoblastic leukaemia. British Journal of Haematology, 167(1), 87-99. https://doi.org/10.1111/bjh.13011
Dandekar, Smita ; Romanos-Sirakis, Eleny ; Pais, Faye ; Bhatla, Teena ; Jones, Courtney ; Bourgeois, Wallace ; Hunger, Stephen P. ; Raetz, Elizabeth A. ; Hermiston, Michelle L. ; Dasgupta, Ramanuj ; Morrison, Debra J. ; Carroll, William L. / Wnt inhibition leads to improved chemosensitivity in paediatric acute lymphoblastic leukaemia. In: British Journal of Haematology. 2014 ; Vol. 167, No. 1. pp. 87-99.
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Dandekar, S, Romanos-Sirakis, E, Pais, F, Bhatla, T, Jones, C, Bourgeois, W, Hunger, SP, Raetz, EA, Hermiston, ML, Dasgupta, R, Morrison, DJ & Carroll, WL 2014, 'Wnt inhibition leads to improved chemosensitivity in paediatric acute lymphoblastic leukaemia', British Journal of Haematology, vol. 167, no. 1, pp. 87-99. https://doi.org/10.1111/bjh.13011

Wnt inhibition leads to improved chemosensitivity in paediatric acute lymphoblastic leukaemia. / Dandekar, Smita; Romanos-Sirakis, Eleny; Pais, Faye; Bhatla, Teena; Jones, Courtney; Bourgeois, Wallace; Hunger, Stephen P.; Raetz, Elizabeth A.; Hermiston, Michelle L.; Dasgupta, Ramanuj; Morrison, Debra J.; Carroll, William L.

In: British Journal of Haematology, Vol. 167, No. 1, 01.10.2014, p. 87-99.

Research output: Contribution to journalArticle

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AU - Dandekar, Smita

AU - Romanos-Sirakis, Eleny

AU - Pais, Faye

AU - Bhatla, Teena

AU - Jones, Courtney

AU - Bourgeois, Wallace

AU - Hunger, Stephen P.

AU - Raetz, Elizabeth A.

AU - Hermiston, Michelle L.

AU - Dasgupta, Ramanuj

AU - Morrison, Debra J.

AU - Carroll, William L.

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N2 - Summary: 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.

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