Improvement of Rituximab Efficiency in Chronic Lymphocytic Leukemia by CpG-Mediated Upregulation of CD20 Expression Independently of PU.1

• Published in: Annals of the New York Academy of Sciences 2009-09, Vol.1173 (1), p.721-728
• Main Authors: Mankaï, Amani, Buhé, Virginie, Hammadi, Mariam, Youinou, Pierre, Ghedira, Ibtissem, Berthou, Christian, Bordron, Anne
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20 - genetics; Antigens, CD20 - immunology; Antigens, CD20 - metabolism; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; B-Lymphocytes - drug effects; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; Blotting, Western; CD20; Cell Line, Tumor; Cells, Cultured; Chronic lymphocytic leukemia; CpG; Cytokines; Effectiveness; Female; Flow Cytometry; Gene expression; Gene Expression Regulation, Leukemic - drug effects; Genes; Humans; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Leukemias; Lymphocytes; Male; Middle Aged; Oligodeoxyribonucleotides - pharmacology; Oligonucleotides; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; PU.1 transcription factor; Reverse Transcriptase Polymerase Chain Reaction; Rituximab; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription, Genetic - drug effects; Tumors; Up-Regulation - drug effects
• ISSN: 0077-8923; 1749-6632
• DOI: 10.1111/j.1749-6632.2009.04614.x

Lipopolysaccharide (LPS), CpG‐containing phosphothioate oligonucleotides (CpG) and various cytokines impact chronic lymphocytic leukemia (CLL) B cells. For example, they influence cell cycle entry, expression of co‐receptors, and CD20. Rituximab (RTX), for which CD20 molecule is the target, proved to be less efficient in CLL than in lymphoma. This is accounted for by a lower CD20 level in the former than in the latter B lymphocytes. CD20 transcription is mediated by four transcription factors, of which only purine‐rich box‐1 (PU.1) is reduced in CLL. We thus examined the effects of LPS, CpG, tumor necrosis factor‐alpha, interferon‐alpha, interleukin (IL)‐3, IL‐4, IL‐21, granulocyte macrophage‐colony stimulating factor (CSF), and granulocyte‐CSF on the transcription of PU.1, and the subsequent expression of CD20. It appeared that CpG was unique in that it raised the membrane expression of CD20 on malignant B cells, owing to a PU.1 independent increase in its gene transcription. Moreover, RTX‐induced complement‐mediated lysis was also ameliorated. Thus, CpG accelerates the transcription of CD20 independently of PU.1, and thereby improves the efficacy of RTX in CLL.