Potassium/sodium cation carriers robustly up-regulate CD20 antigen by targeting MYC, and synergize with anti-CD20 immunotherapies to eliminate malignant B cells
Anna Torun,
Aleksandra Zdanowicz,
Nina Miazek-Zapala,
Piotr Zapala,
Bhaskar Pradhan,
Marta Jedrzejczyk,
Andrzej Ciechanowicz,
Zofia Pilch,
Marcin Skorzynski,
Mikołaj Słabicki,
Grzegorz Rymkiewicz,
Joanna Barankiewicz,
Claudio Martines,
Luca Laurenti,
Marta Struga,
Magdalena Winiarska,
Jakub Golab,
Magdalena Kucia,
Mariusz Z. Ratajczak,
Adam Huczynski,
Dinis P. Calado,
Dimitar G. Efremov,
Abdessamad Zerrouqi,
Beata Pyrzynska
Affiliations
Anna Torun
Medical University of Warsaw, Warsaw
Aleksandra Zdanowicz
Medical University of Warsaw, Warsaw, Poland; Doctoral School, Medical University of Warsaw, Warsaw
Nina Miazek-Zapala
Medical University of Warsaw, Warsaw
Piotr Zapala
Medical University of Warsaw, Warsaw
Bhaskar Pradhan
Medical University of Warsaw, Warsaw, Poland; Doctoral School, Medical University of Warsaw, Warsaw
Marta Jedrzejczyk
Adam Mickiewicz University, Poznan
Andrzej Ciechanowicz
Medical University of Warsaw, Warsaw
Zofia Pilch
Medical University of Warsaw, Warsaw
Marcin Skorzynski
Medical University of Warsaw, Warsaw
Mikołaj Słabicki
Broad Institute of MIT and Harvard, Cambridge, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA
Grzegorz Rymkiewicz
Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw
Joanna Barankiewicz
Institute of Hematology and Transfusion Medicine, Warsaw
Claudio Martines
Molecular Hematology Unit, International Centre for Genetic Engineering and Biotechnology, Trieste
Luca Laurenti
Hematology Unit, Fundazione Policlinico Universitario A Gemelli IRCCS, Rome
Marta Struga
Medical University of Warsaw, Warsaw
Magdalena Winiarska
Medical University of Warsaw, Warsaw
Jakub Golab
Medical University of Warsaw, Warsaw
Magdalena Kucia
Medical University of Warsaw, Warsaw
Mariusz Z. Ratajczak
Medical University of Warsaw, Warsaw
Adam Huczynski
Adam Mickiewicz University, Poznan
Dinis P. Calado
The Francis Crick Institute, London, United Kingdom
Dimitar G. Efremov
Molecular Hematology Unit, International Centre for Genetic Engineering and Biotechnology, Trieste
Abdessamad Zerrouqi
Medical University of Warsaw, Warsaw, Poland; Senior authors
Beata Pyrzynska
Medical University of Warsaw, Warsaw, Poland; Senior authors
Our investigation uncovers that nanomolar concentrations of salinomycin, monensin, nigericin, and narasin (a group of potassium/sodium cation carriers) robustly enhance surface expression of CD20 antigen in B-cell-derived tumor cells, including primary malignant cells of chronic lymphocytic leukemia and diffuse large B-cell lymphoma. Experiments in vitro, ex vivo, and animal model reveal a novel approach of combining salinomycin or monensin with therapeutic anti-CD20 monoclonal antibodies or anti-CD20 CAR-T cells, significantly improving non- Hodgkin lymphoma (NHL) therapy. The results of RNA-seq, genetic editing, and chemical inhibition delineate the molecular mechanism of CD20 upregulation, at least partially, to the downregulation of MYC, the transcriptional repressor of the MS4A1 gene encoding CD20. Our findings propose the cation carriers as compounds targeting MYC oncogene, which can be combined with anti-CD20 antibodies or adoptive cellular therapies to treat NHL and mitigate resistance, which frequently depends on the CD20 antigen loss, offering new solutions to improve patient outcomes.
