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Blood Adv. 2017 Nov 9;1(24):2257-2268. doi: 10.1182/bloodadvances.2017010215. eCollection 2017 Nov 14.

Crosstalk between ROR1 and BCR pathways defines novel treatment strategies in mantle cell lymphoma.

Author information

BioMediTech Institute and.
Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
Centre de Recherche en Cancérologie et Immunologie Nantes Angers, INSERM, Centre National de la Recherche Scientifique, Université de Nantes, Centre Hospitalier Universitaire de Nantes, Nantes, France.
Department of Immunotechnology, Faculty of Engineering, and.
Department of Oncology and Pathology, Institute of Clinical Sciences, Lund University, Lund, Sweden.
Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland; and.
Science for Life Laboratory, Department of Oncology and Pathology, Karolinska Institutet, Solna, Sweden.


Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin B-cell lymphoma with poor prognosis due to drug resistance. Introduction of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib has markedly improved MCL therapy outcome, but drug resistance remains a challenge. The selective cell-surface expression of oncogenic receptor tyrosine kinase-like orphan receptor 1 (ROR1) pseudokinase in hematological malignancies has made this receptor a promising candidate for targeted therapy. We sought to identify the molecular mechanism underlying divergent ROR1-mediated apoptotic responses in MCL cell lines and primary samples. We show that targeting ROR1 expression resulted in downregulation of NF-κB p65 levels and that activation of the NF-κB pathway can antagonize ROR1-mediated apoptotic responses. High-throughput drug-sensitivity testing of MCL cells before and after ROR1 targeting revealed synergistic effects between cotargeting of ROR1 and the B-cell antigen receptor (BCR) or Bcl-2 family, underlining the high potential for ROR1-targeted therapies in overcoming MCL drug resistance. However, inhibition of the BCR pathway by targeted drugs such as ibrutinib can impair ROR1 expression and consequently ROR1-targeted treatments, underscoring the importance of inhibiting both pathways to augment cancer cell killing. Considering the central role of NF-κB pathway activation in B-cell malignancies, this study highlights key factors that can modulate ROR1-targeted treatments in hematological cancers.

Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

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