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Dishevelled proteins are significantly upregulated in chronic lymphocytic leukaemia

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Tumor Biology

Abstract

Dishevelled (DVL) proteins are components of the Wnt signalling pathways, and increased expression is associated with various malignancies. Information on DVLs in chronic lymphatic leukaemia (CLL) is limited. The aim of the present study was to investigate the role of DVLs in CLL cells and association with Wnt pathways downstream of ROR1. DVL1, 2 and 3 were exclusively expressed in CLL cells as compared to normal peripheral blood mononuclear cells (PBMCs). The expression of DVL1 and DVL3 proteins was significantly more pronounced in progressive than in non-progressive disease (p < 0.01), whereas the level of DVL2 was significantly higher in non-progressive as compared to progressive disease (p < 0.001). Treatment of CLL cells with anti-ROR1 specific monoclonal antibodies induced dephosphorylation of ROR1 as well as of tyrosine and serine residues of both DVL2 and DVL3. However, gene silencing of DVLs in the CLL cell line (EHEB) did not induce detectable apoptosis. Non-progressive CLL patients had a different protein activity pattern with regard to Wnt signalling pathway proteins as GSK-3β, β-catenin and AKT as compared to progressive disease. The DVL2 protein may play a role in the activation of signalling pathways in CLL during early stages of the disease, while DVL1 and 3 may have a role in later phases of the leukaemia.

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Acknowledgments

This study was supported by grants from CLL Global Research Foundation, the Cancer and Allergy Foundation (149351, 149746, 150288), the Swedish Research Council (K2013-64X-21464-04-3), the Swedish Cancer Society (CAN 2009/852), the Cancer Society in Stockholm (121332), the King Gustav Vth Jubilee Fund (124272) and the Stockholm County Council (20120051). The secretarial help from Leila Relander is highly appreciated.

Authors’ contributions

ASK and AM designed the study, performed experiments, interpreted data and wrote the manuscript; MHF performed experiments and read the manuscript; AHDM read the manuscript; HM, AÖ and LH provided clinical samples and all read the manuscript; and HM supervised the study.

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Authors and Affiliations

  1. Department of Oncology-Pathology, Immune and Gene Therapy Lab, Cancer Center Karolinska (CCK), Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden

    Abdul Salam Khan, Mohammad Hojjat-Farsangi, Amir Hossein Daneshmanesh, Lotta Hansson, Parviz Kokhaei, Anders Österborg, Håkan Mellstedt & Ali Moshfegh

  2. Department of Hematology, Karolinska University Hospital Solna, Stockholm, Sweden

    Lotta Hansson & Anders Österborg

  3. Cancer Research Center and Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran

    Parviz Kokhaei

  4. Cancer Centre Karolinska, Department of Oncology, Karolinska University Hospital Solna, SE-171 76, Stockholm, Sweden

    Håkan Mellstedt

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  1. Abdul Salam Khan
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Correspondence to Håkan Mellstedt.

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Approval by the regional ethics committee (www.epn.se) was obtained as well as oral and written informed consent from the donors in accordance with the Helsinki Declaration.

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Khan, A.S., Hojjat-Farsangi, M., Daneshmanesh, A.H. et al. Dishevelled proteins are significantly upregulated in chronic lymphocytic leukaemia. Tumor Biol. 37, 11947–11957 (2016). https://doi.org/10.1007/s13277-016-5039-5

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