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Wnt5a and ROR1 activate non-canonical Wnt signaling via RhoA in TCF3-PBX1 acute lymphoblastic leukemia and highlight new treatment strategies via Bcl-2 co-targeting

Oncogene volume 38, pages 3288–3300 (2019)Cite this article

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Abstract

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with TCF3-PBX1 fusion gene expression has constitutively elevated levels of Wnt16b and ROR1 (receptor tyrosine kinase-like orphan receptor), a ligand and a receptor from the Wnt signaling pathway, respectively. Although survival rate is usually high after the initial chemotherapy, many TCF3-PBX1 BCP-ALL patients relapse and subsequently develop treatment resistance, resulting in poor prognosis. Here, we aimed to investigate the molecular signaling associated with Wnt16b and ROR1 overexpression in TCF3-PBX1 cell lines and primary samples, and to identify effective treatment options via ROR1 targeting. We detected higher ROR1 expression on TCF3-PBX1 leukemic cells even at a later stage of patient relapse, providing a strong rationale for the use of ROR1-targeted therapy. We found that Wnt5a-ROR1 signaling enhances proliferation of TCF3-PBX1 cells via RhoA/Rac1 GTPases activation and STAT3 upregulation. Wnt16b also activated the RhoA/Rac1 signaling cascade suggesting the activation of a non-canonical Wnt pathway in TCF3-PBX1 cells. Wnt16 could interact with ROR1 but not in TCF3-PBX1 cells, suggesting that Wnt5a is the ligand signaling via ROR1 in TCF3-PBX1 cells. By high throughput drug-sensitivity testing of TCF3-PBX1 cells before and after ROR1 knockdown we found that targeting ROR1 significantly improves the therapeutic efficacy of Bcl-2 family inhibitors venetoclax and navitoclax, and this synergism was confirmed ex vivo using a drug-resistant primary sample from a relapsed TCF3-PBX1 patient. Our work underlines a new type of targeted combination therapy that could be clinically advantageous for patients with TCF3-PBX1 BCP-ALL.

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Acknowledgements

We thank the patients for donating their samples to support our research, the staff of High Throughput Biomedicine Unit at Institute for Molecular Medicine Finland, the Tampere facility of Virus Production and Tampere facility of Flow Cytometry for their service.

Funding

This work was supported by the Doctoral Program in Medicine and Life Sciences at University of Tampere, Academy of Finland, Center of Excellence for Translational Cancer Biology, and the Sigrid Juselius Foundation.

Author contributions

HK, RP, WN, VH designed and performed the experiments. HB performed the bioinformatics analyses. DU wrote the manuscript and supervised the work. CH contributed with clinical samples and critical discussion on the manuscript. AM contributed with DSRT experiments and critical discussions of the manuscript.

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  1. BioMediTech Institute and Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland

    Hanna Karvonen, Robert Perttilä, Wilhelmiina Niininen, Veera Hautanen, Harlan Barker & Daniela Ungureanu

  2. Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland

    Astrid Murumägi & Caroline A. Heckman

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Karvonen, H., Perttilä, R., Niininen, W. et al. Wnt5a and ROR1 activate non-canonical Wnt signaling via RhoA in TCF3-PBX1 acute lymphoblastic leukemia and highlight new treatment strategies via Bcl-2 co-targeting. Oncogene 38, 3288–3300 (2019). https://doi.org/10.1038/s41388-018-0670-9

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