Page 18 - Programa Educacional Congres SEHH-SETH 2017

Epstein-Barr virus, although the pathogenetic role of this virus remains controversial. The genome of all BL is characterized by the invariable presence of chro- mosomal translocations involving one of the immuno- globulin loci and the MYC proto-oncogene leading to its escape from the BCL6-mediated transcriptional repression that normally prevents MYC expression in DZ B-cells. MYC is a DNA-binding transcriptional regulator of proliferation, cell growth, differentiation and apop- tosis, as well as DNA replication independently of its transcriptional activity(1).
In addition to the translocations, ~ 70% of BL cases display mutations of the TCF3 transcription factor –lead- ing to escape from its negative regulator ID3– or inac- tivating mutations in ID3, which prevent its modulatory function on TCF3(4).The resulting dysregulated activity of TCF3 appears to promote antigen-independent “tonic” BCR signaling and, as a consequence, to activate the PI3K pathway, which is not active in normal DZ B-cells. In addition, TCF3 affects cell proliferation by transactiva- tion of CCND3, a D-type cyclin that regulates the G1-S phase transition and is necessary for GC formation and expansion. Finally, one third of human BL cases display inactivating mutations of several tumor suppressors in- cluding TP53, PTEN and CDKN2A(4), as well as mutations affecting the Gα13-dependent pathway that is involved in modulating GC B-cell migration and con nement (discussed in the “GCB-DLBCL” section).
❯ Follicular lymphoma
The t(14;18) translocation, that is detectable in more than 80% of cases, places the BCL2 gene under the control of the IGH locus. Thus, translocations affect- ing BCL2 occur early during B-cell development, but its dysregulation contributes to lymphomagenesis at later stages, during the GC reaction, possibly as a consequence of antigen stimulation. In GC B-cells, the juxtaposition of the IGH regulatory regions leads to the escape of BCL2 from the BCL6-mediated repression and to its ectopic expression, thus activating an anti- apoptotic program(1).
Recent genomic studies revealed that mono- or bi- allelic inactivation of the MLL2 gene represent a sec- ond highly recurrent genetic lesion of follicular lym- phoma, being detected in more than 80% of cases(5,6). These alterations interfere with the ability of MLL2 to act as an H3K4 methyl-transferase. Since H3K4 methylation
is a marker of transcriptional activation, defective MLL2 expression or activity may interfere with the deposition of this histone markers and lead to a consequent de- rangement of the cell transcriptional program. Inter- estingly, MLL2 inactivation appears to be a very early event in FL pathogenesis, which indicates that early changes in the epigenome, perhaps in combination with the dysregulated expression of BCL2, may facili- tate malignant transformation in the GC(7). Of note, alteration of other chromatin modi ers, including EZH2 (in ~ 27% of cases) and the acetyl-transferases CREBBP and EP300 (in ~ 40%), are also common events both in FL and DLBCL (see below).
❯ Diffuse large B-cell lymphoma
DLBCL include 2 major subtypes: GCB-DLBCL, deriving from GC LZ B-cells, and ABC-DLBCL originating from a later stage of GC differentiation when B-cells are com- mitted to plasmablastic differentiation(2). These DLBCL subtypes display subtype-speci c genetic aberrations, as well as common ones, including those involving BCL6 dysregulation, chromatin modi ers and immune escape.
The BCL6 locus is targeted by chromosomal translo- cations that place the intact protein coding sequence of BCL6 downstream of heterologous regulatory re- gions that comprise the IGH locus, as well as the pro- moters of a variety of genes. This “promoter substitu- tion” mechanism prevents the down-regulation of BCL6 expression that is normally associated with post-GC dif- ferentiation. In addition, the binding of BCL6 or IRF4 to the BCL6 promoter can be impaired by mutations that contribute to dysregulate BCL6 expression by interfer- ing with its auto-regulatory circuit,or the CD40-induced, IRF4-mediated repression(8). Overall, genetic alterations that affect the BCL6 locus and lead to its dysregulated expression are common events in DLBCL (~ 30%). Dys- regulated BCL6 expression and/or activity is also sus- tained by indirect mechanisms, including loss-of-func- tion alterations in the acetyl-transferases CREBBP and EP300, which are involved in the acetylation-mediated inactivation of BCL6(9), gain-of-function mutations in its positive transcriptional regulator MEF2B(10), and inacti- vation of FBXO11(11), a speci c adaptor for BCL6 ubiqui- tylation and degradation.
Alterations in genes encoding chromatin modi ers are represented by genetic inactivation of the ace-
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LIX Congreso Nacional SEHH-XXXIII Congreso Nacional SETH / Programa Educacional