Potassium/sodium cation carriers robustly up-regulate CD20 antigen by targeting MYC, and synergize with anti-CD20 immunotherapies to eliminate malignant B cells
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 chimeric antigen receptor T cells, significantly improving non-Hodgkin lymphoma therapy. The results of RNA sequencing, 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 non-Hodgkin lymphoma and mitigate resistance, which frequently depends on the CD20 antigen loss, offering new solutions to improve patient outcomes.
Authors
- Abdessamad Zerrouqi (ORCID: https://orcid.org/0000-0002-2628-473X)
- Marta Jędrzejczyk (ORCID: https://orcid.org/0000-0003-4214-569X)
- Magda Kucia (ORCID: https://orcid.org/0000-0002-9110-5048)
- Claudio Martines (ORCID: https://orcid.org/0000-0001-7136-7174)
- Marcin Skorzynski (ORCID: https://orcid.org/0000-0001-6665-9041)
- Dimitar G. Efremov (ORCID: https://orcid.org/0000-0001-9081-5462)
- Bhaskar Pradhan (ORCID: https://orcid.org/0000-0003-2751-1428)
- Beata Pyrzyńska (ORCID: https://orcid.org/0000-0002-0490-618X)
- Zofia Pilch (ORCID: https://orcid.org/0000-0002-8214-7158)
- Adam Huczyński (ORCID: https://orcid.org/0000-0003-4770-215X)
- Nina Miązek-Zapała
- Aleksandra Zdanowicz (ORCID: https://orcid.org/0000-0002-0875-2608)
- Piotr Zapała (ORCID: https://orcid.org/0000-0002-0569-4203)
- Jakub Gołąb (ORCID: https://orcid.org/0000-0002-2830-5100)
- Dinis Pedro Calado (ORCID: https://orcid.org/0000-0001-8239-7184)
- Mikołaj Słabicki (ORCID: https://orcid.org/0000-0001-6317-9296)
- Anna Torun
- Grzegorz Rymkiewicz (ORCID: https://orcid.org/0000-0002-3478-8014)
- Marta Struga (ORCID: https://orcid.org/0000-0002-0181-3607)
- Mariusz Z. Ratajczak (ORCID: https://orcid.org/0000-0002-0071-0198)
- Andrzej Ciechanowicz (ORCID: https://orcid.org/0000-0002-3804-440X)
- Luca Laurenti (ORCID: https://orcid.org/0000-0002-4527-4131)
- Magdalena Winiarska (ORCID: https://orcid.org/0000-0001-5605-3329)
- Joanna Barankiewicz (ORCID: https://orcid.org/0000-0002-5029-9173)
Institutions
- Broad Institute (US)
- Medical University of Warsaw (PL)
- The Francis Crick Institute (GB)
- Agostino Gemelli University Polyclinic (IT)
- Dana-Farber Cancer Institute (US)
- National Institute of Oncology (HU)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Marymount University (US)
- Adam Mickiewicz University in Poznań (PL)
- International Centre for Genetic Engineering and Biotechnology (IT)
Publication Details
- Journal
- Haematologica
- Published
- 2024-12-19
- DOI
- https://doi.org/10.3324/haematol.2024.285826
- Citations
- 3
- Primary Topic
- Toxin Mechanisms and Immunotoxins
- Type
- article
- Field-Weighted Citation Impact
- 0.72