H e m a t o lo g y E d u c a t io n - European Hematology Association

of cases) 46 and amplifications of the region encompassing
the mir-17-92 microRNA cluster on chromosome 13,
which has also been shown to suppress PTEN. 60
ABC-DLBCL
Several genetic abnormalities are observed almost
exclusively in ABC-DLBCL, including amplifications of
the BCL2 locus on 18q24; 61,62 mutations within the NFκB
(CARD11, TNFAIP3/A20), 63,64 BCR (CD79A/B) 65 and
JAK/STAT (MYD88) signaling pathways; inactivating
mutations and deletions of PRDM1; 27,28,66 and deletion or
lack of expression of the CDKN2A tumor suppressor
gene. In addition, chromosomal translocations deregulating
the BCL6 oncogene are found more frequently in
this subtype. Mutations of ATM have also been reported
in a small subset of cases. 67,68
NF-κB pathway lesions
A prominent feature of ABC-DLBCL is the constitutive
activation of the NF-κB signaling pathway, as
revealed by the selective enrichment in NF-κB target
genes expression, and by the requirement of NF-κB for
the proliferation and survival of ABC-, but not GCB-
DLBCL cell lines. 85 Over the past two years, a number of
studies have provided a genetic basis for this phenotypic
characteristic by identifying multiple oncogenic alterations
that affect positive and negative regulators of NFκB,
specifically in this disease subtype. In up to 30% of
the cases, biallelic mutations and/or deletions inactivate
the TNFAIP3 gene, which encodes for the negative regulator
A20, thus preventing termination of NF-κB
responses. 63,86 In ~9% of patients, CARD11 is targeted
by oncogenic mutations that cluster within the protein
coiled-coil domain and enhance its ability to transactivate
NF-κB target genes. 63,64 Less commonly, mutations
were found in a variety of other genes encoding for NF-κB
components (among others, TRAF2 and TRAF5). 63
London, United Kingdom, June 9-12, 2011
ABC-DLBCL activate NF-κB also via a chronic form of
active BCR signaling, which is associated with somatic
mutations in the immunoreceptor tyrosine-based activation
motif (ITAM) signaling modules of CD79B and
CD79A (> 20% of patients). 65 Since BCR signaling can
also trigger other pathways, such as MAPK and PI3K,
future studies will have to address the relative or coordinate
contribution of these pathways to the development
of DLBCL (Figure 2). Finally, oncogenically active
MYD88 mutations were recently reported in almost one
third of all ABC-DLBCLs, where they mostly target an
evolutionarily invariant residue within the TIR (Toll/IL1
receptor) domain. 87 Besides activating NF-κB, mutations
of MYD88 induce JAK/STAT3 transcriptional responses,
also a phenotypic trait of ABC-DLBCL. 88,89 Collectively,
lesions converging on the NF-κB pathway account for
greater than 50% of all ABC-DLBCL. 63
PRDM1 inactivation
In up to 25% of ABC-DLBCLs, the PRDM1 gene is
inactivated by a variety of genetic lesions, including
truncating point mutations, inactivating missense mutations,
and/or genomic deletions. 27,28,66 An additional sizeable
fraction of cases has lost PRDM1 protein expression
due to transcriptional repression by constitutively
active, translocated BCL6 alleles. 27,66 The PRDM1 gene
encodes for a zinc finger transcriptional repressor that is
expressed in a subset of GC B cells undergoing plasma
cell differentiation and in all plasma cells, 82,83 and which
is essential for terminal B cell differentiation. 84 Thus,
PRDM1 functions as a tumor suppressor gene and may
favor malignant transformation by blocking post-GC
differentiation of B cells. In line with these findings,
rearrangements of the BCL6 locus and genetic lesions of
PRDM1 are mutually exclusive in ABC-DLBCL, indicating
that BCL6 deregulation and PRDM1 inactivation
represent alternative oncogenic mechanisms converging
Figure 2. Pathway lesions in ABC-
DLBCL. Schematic representation of
a germinal center centrocyte,
expressing a functional surface BCR,
CD40 receptor and Toll-like receptor
(TLR). In normal B cells, engagement
of these signaling pathways leads to
activation of NF-κB and transcription
of its targets genes including IRF4
and TNFAIP3/A20. IRF4, in turn,
downregulate BCL6 expression, allowing
the release of the master plasma
cell regulator PRDM1 and the development
into a differentiated plasma
cell. In DLBCL, a variety of genetic
lesions disrupt this circuit at multiple
levels predominantly in the ABC-subtype,
and contribute to lymphomagenesis
by favoring the anti-apoptotic
function of NF-κB while blocking terminal
B cell differentiation. Crosses
indicate inactivating mutations/deletions;
lightning bolts denote activating
mutations.
Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 195 |