Transient expression of Bcl6 is sufficient for oncogenic function and induction of mature B-cell lymphoma

Nat Commun. 2014 Jun 2;5:3904. doi: 10.1038/ncomms4904.

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma and can be separated into two subtypes based upon molecular features with similarities to germinal centre B-cells (GCB-like) or activated B-cells (ABC-like). Here we identify gain of 3q27.2 as being significantly associated with adverse outcome in DLBCL and linked with the ABC-like subtype. This lesion includes the BCL6 oncogene, but does not alter BCL6 transcript levels or target-gene repression. Separately, we identify expression of BCL6 in a subset of human haematopoietic stem/progenitor cells (HSPCs). We therefore hypothesize that BCL6 may act by 'hit-and-run' oncogenesis. We model this hit-and-run mechanism by transiently expressing Bcl6 within murine HSPCs, and find that it causes mature B-cell lymphomas that lack Bcl6 expression and target-gene repression, are transcriptionally similar to post-GCB cells, and show epigenetic changes that are conserved from HSPCs to mature B-cells. Together, these results suggest that BCL6 may function in a 'hit-and-run' role in lymphomagenesis.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Murine-Derived / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • B-Lymphocytes / metabolism*
  • Cyclophosphamide / therapeutic use
  • DNA Copy Number Variations
  • DNA Methylation
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Doxorubicin / therapeutic use
  • Epigenesis, Genetic
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Hematopoietic Stem Cells / metabolism*
  • Humans
  • Lymphoma, Large B-Cell, Diffuse / drug therapy
  • Lymphoma, Large B-Cell, Diffuse / genetics*
  • Lymphoma, Large B-Cell, Diffuse / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Phenotype
  • Prednisone / therapeutic use
  • Prognosis
  • Proto-Oncogene Proteins c-bcl-6
  • Rituximab
  • Vincristine / therapeutic use

Substances

  • Antibodies, Monoclonal, Murine-Derived
  • BCL6 protein, human
  • Bcl6 protein, mouse
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins c-bcl-6
  • R-CHOP protocol
  • Rituximab
  • Vincristine
  • Doxorubicin
  • Cyclophosphamide
  • Prednisone

Supplementary concepts

  • CHOP protocol

Associated data

  • GEO/GSE36503
  • GEO/GSE56310