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

Ann N Y Acad Sci. 2009 Sep;1173:721-8. doi: 10.1111/j.1749-6632.2009.04614.x.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Cell Line, Tumor
  • Cells, Cultured
  • Female
  • Flow Cytometry
  • Gene Expression Regulation, Leukemic / drug effects
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Male
  • Middle Aged
  • Oligodeoxyribonucleotides / pharmacology*
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rituximab
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism
  • Transcription, Genetic / drug effects
  • Up-Regulation / drug effects

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Murine-Derived
  • Antigens, CD20
  • Antineoplastic Agents
  • CPG-oligonucleotide
  • Oligodeoxyribonucleotides
  • Proto-Oncogene Proteins
  • Trans-Activators
  • proto-oncogene protein Spi-1
  • Rituximab