Engagement of the B-cell receptor of chronic lymphocytic leukemia cells drives global and MYC-specific mRNA translation

Blood. 2016 Jan 28;127(4):449-57. doi: 10.1182/blood-2015-07-660969. Epub 2015 Oct 21.

Abstract

Antigenic stimulation via the B-cell receptor (BCR) is a major driver of the proliferation and survival of chronic lymphocytic leukemia (CLL) cells. However, the precise mechanisms by which BCR stimulation leads to accumulation of malignant cells remain incompletely understood. Here, we investigated the ability of BCR stimulation to increase messenger RNA (mRNA) translation, which can promote carcinogenesis by effects on both global mRNA translation and upregulated expression of specific oncoproteins. Re-analysis of gene expression profiles revealed striking upregulation of pathways linked to mRNA translation both in CLL cells derived from lymph nodes, the major site of antigen stimulation in vivo, and after BCR stimulation in vitro. Anti-IgM significantly increased mRNA translation in primary CLL cells, measured using bulk metabolic labeling and a novel flow cytometry assay to quantify responses at a single-cell level. These translational responses were suppressed by inhibitors of BTK (ibrutinib) and SYK (tamatinib). Anti-IgM-induced mRNA translation was associated with increased expression of translation initiation factors eIF4A and eIF4GI, and reduced expression of the eIF4A inhibitor, PDCD4. Anti-IgM also increased mRNA translation in normal blood B cells, but without clear modulatory effects on these factors. In addition, anti-IgM increased translation of mRNA-encoding MYC, a major driver of disease progression. mRNA translation is likely to be an important mediator of the growth-promoting effects of antigen stimulation acting, at least in part, via translational induction of MYC. Differences in mechanisms of translational regulation in CLL and normal B cells may provide opportunities for selective therapeutic attack.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase
  • Antibodies, Anti-Idiotypic / immunology
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • Cell Line, Tumor
  • Gene Expression Regulation, Leukemic*
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Protein Biosynthesis / drug effects
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Proto-Oncogene Proteins c-myc / genetics*
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology
  • RNA, Messenger / genetics*
  • Receptors, Antigen, B-Cell / genetics
  • Receptors, Antigen, B-Cell / immunology*
  • Syk Kinase
  • Tumor Cells, Cultured

Substances

  • Antibodies, Anti-Idiotypic
  • Intracellular Signaling Peptides and Proteins
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-myc
  • Pyrazoles
  • Pyrimidines
  • RNA, Messenger
  • Receptors, Antigen, B-Cell
  • anti-IgM
  • ibrutinib
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • SYK protein, human
  • Syk Kinase