Blood, 15 April 2003, Vol. 101, No. 8, pp. 2902-2902
Lack of BCL-6 self-control fuels
lymphomagenesis
Chromosomal translocations affecting the BCL-6
proto-oncogene, which are the most common, specific genetic alteration
found in diffuse large B-cell lymphomas (DLBCLs), were first identified by Dalla-Favera and coworkers. Targeted deletion of BCL-6
revealed its critical physiologic role for the formation of the
germinal center (GC) and the production of memory T cells.
Signals emanating from pathways associated with lymphocytic
differentiation, such as IgM engagement or CD40-CD40L interaction,
down-regulate BCL-6 expression. The Bcl-6 protein, a
transcriptional repressor that is expressed in the mature GC,
suppresses genes involved in apoptosis, cell cycle arrest, and in
lymphocytic mitogenesis and differentiation. These observations
indicate that BCL-6 inhibits lymphocytic differentiation and, hence, BCL-6 deregulated expression in DLBCLs
contributes to the maintenance of the undifferentiated lymphoma phenotype.
In addition to the chromosomal translocations activating
BCL-6 in DLBCLs, the BCL-6 locus is altered by
somatic mutations that are intriguingly also found in normal GC B
cells. While the genesis of these BCL-6 mutations, which
cluster around the transcription initiation site, are associated with
the normal somatic hypermutation mechanism responsible for
immunoglobulin variable sequences, the significance of these mutations
in lymphomagenesis has remained unclear. In this issue, Pasqualucci and
coworkers (page 2914) report mutations of BCL-6, which are
not found in the normal GC, that disrupt negative autoregulation of
BCL-6 in 40% of DLBCL cases. In particular, the 2 Bcl-6 DNA
binding sites located in the noncoding exon 1 are mutated such that
Bcl-6 protein is unable to bind the mutant sites. These observations
are similar to those recently reported by Wang et al (Proc Natl
Acad Sci U S A. 2002;99:15018-15023) supporting the hypothesis that
lack of self-control by BCL-6 contributes to the genesis of DLBCLs.
Chi Van Dang
Johns Hopkins University School of
Medicine
