Pre-B cell receptor-mediated activation of BCL6 induces pre-B cell quiescence through transcriptional repression of MYC

Blood. 2011 Oct 13;118(15):4174-8. doi: 10.1182/blood-2011-01-331181. Epub 2011 Aug 19.

Abstract

Initial cell surface expression of the pre-B cell receptor induces proliferation. After 2 to 5 divisions, however, large pre-BII (Fraction C') cells exit cell cycle to become resting, small pre-BII cells (Fraction D). The mechanism by which pre-BII cells exit cell cycle, however, is currently unclear. The checkpoint at the Fraction C'-D transition is critical for immunoglobulin light chain gene recombination and to prevent malignant transformation into acute lymphoblastic leukemia. Here we demonstrate that inducible activation of pre-B cell receptor signaling induces cell-cycle exit through up-regulation of the transcriptional repressor BCL6. Inducible activation of BCL6 downstream of the pre-B cell receptor results in transcriptional repression of MYC and CCND2. Hence, pre-B cell receptor-mediated activation of BCL6 limits pre-B cell proliferation and induces cellular quiescence at the small pre-BII (Fraction D) stage.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Checkpoints / physiology*
  • Cell Division / physiology*
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cyclin D2 / genetics
  • Cyclin D2 / metabolism
  • DNA-Binding Proteins / biosynthesis*
  • DNA-Binding Proteins / genetics
  • Gene Rearrangement, B-Lymphocyte, Light Chain / physiology
  • Immunoglobulin Light Chains / genetics
  • Immunoglobulin Light Chains / metabolism
  • Mice
  • Mice, Knockout
  • Pre-B Cell Receptors / genetics
  • Pre-B Cell Receptors / metabolism*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor Cells, B-Lymphoid / cytology
  • Precursor Cells, B-Lymphoid / metabolism*
  • Proto-Oncogene Proteins c-bcl-6
  • Proto-Oncogene Proteins c-myc / biosynthesis*
  • Proto-Oncogene Proteins c-myc / genetics
  • Signal Transduction / physiology
  • Transcription, Genetic / physiology*

Substances

  • Bcl6 protein, mouse
  • Ccnd2 protein, mouse
  • Cyclin D2
  • DNA-Binding Proteins
  • Immunoglobulin Light Chains
  • Myc protein, mouse
  • Pre-B Cell Receptors
  • Proto-Oncogene Proteins c-bcl-6
  • Proto-Oncogene Proteins c-myc