Page 36 - Haematologica - Vol. 105 n. 6 - June 2020

Ferrata Storti Foundation
Haematologica 2020 Volume 105(6):1494-1506
The regulation and function of CD20: an “enigma” of B-cell biology and targeted therapy
Gabriela Pavlasova1,2 and Marek Mraz1,2
1Central European Institute of Technology, Masaryk University, Brno and 2Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
ABSTRACT
The introduction of anti-CD20 monoclonal antibodies such as ritux- imab, ofatumumab, or obinutuzumab improved the therapy of B- cell malignancies even though the precise physiological role and regulation of CD20 remains unclear. Furthermore, CD20 expression is highly variable between different B-cell malignancies, patients with the same malignancy, and even between intraclonal subpopulations in an individual patient. Several epigenetic (EZH2, HDAC1/2, HDAC1/4, HDAC6, complex Sin3A-HDAC1) and transcription factors (USF, OCT1/2, PU.1, PiP, ELK1, ETS1, SP1, NFκB, FOXO1, CREM, SMAD2/3) regulating CD20 expression (encoded by MS4A1) have been character- ized. CD20 is induced in the context of microenvironmental interactions by CXCR4/SDF1 (CXCL12) chemokine signaling and the molecular func- tion of CD20 has been linked to the signaling propensity of B-cell receptor (BCR). CD20 has also been shown to interact with multiple other surface proteins on B cells (such as CD40, MHCII, CD53, CD81, CD82, and CBP). Current efforts to combine anti-CD20 monoclonal antibodies with BCR signaling inhibitors targeting BTK or PI3K (ibrutinib, acalabrutinib, idelal- isib, duvelisib) or BH3-mimetics (venetoclax) lead to the necessity to bet- ter understand both the mechanisms of regulation and the biological func- tions of CD20. This is underscored by the observation that CD20 is decreased in response to the “BCR inhibitor” ibrutinib which largely pre- vents its successful combination with rituximab. Several small molecules (such as histone deacetylase inhibitors, DNA methyl-transferase inhibitors, aurora kinase A/B inhibitors, farnesyltransferase inhibitors, FOXO1 inhibitors, and bryostatin-1) are being tested to upregulate cell- surface CD20 levels and increase the efficacy of anti-CD20 monoclonal antibodies. Herein, we review the current understanding of CD20 func- tion, and the mechanisms of its regulation in normal and malignant B cells, highlighting the therapeutic implications.
Introduction
The approval of the anti-CD20 antibody rituximab by the Food and Drug Administration in 1997 was a conceptual breakthrough in the treatment of B-cell malignancies. Rituximab improved progression-free survival and overall survival rates when added to chemotherapy in “mature” B-cell leukemias and lymphomas such as chronic lymphocytic leukemia (CLL), follicular lymphoma, and diffuse large B-cell lymphoma (DLBCL), and this proved that monoclonal antibodies could be used in cancer treatment.1 Additionally, rituximab maintenance therapy has been introduced for some of these diseases. Based on the success of rituximab, new engineered anti-CD20 monoclonal antibodies, namely ofatumumab and obinu- tuzumab, were developed. Preclinical studies suggest that these new anti-CD20 monoclonal antibodies are superior to rituximab for some mechanisms of action.2 Anti-CD20 monoclonal antibodies might act through several mechanisms (Figure 1) including complement-dependent cytotoxicity (CDC), complement-dependent cellular cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), antibody-
Correspondence:
MAREK MRAZ
marek.mraz@email.cz
Received: Nevember 22, 2019. Accepted: April 15, 2020.
doi:10.3324/haematol.2019.243543
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/6/1494
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