Page 17 - Programa Educacional Congres SEHH-SETH 2017

Mechanisms of germinal-center derived lymphomagenesis
❯ Introduction
Most of B-cell non-Hodgkin lymphomas (B-NHL), the ex- ception being a subset of mantle cell lymphoma (MCL), derive from mature B cells that have transited through the germinal center (GC), but display heterogeneous phenotypes that re ect both their derivation from dis- tinct phases of the GC reaction, and the occurrence of distinct genetic lesions.We will focus on the cell of origin and pathogenesis of the most common GC-derived tumors, Burkitt lymphoma (BL), follicular lymphoma (FL) and common subtypes of diffuse large B-cell lympho- ma (DLBCL). For a more extensive review see(1).
❯ Cell-of-origin
GC, the histological structure dedicated to the genera- tion and selection of B-cells that produce high af nity antibodies(1), are made of a dark zone (DZ), formed by highly proliferating B cells that undergo immunoglobu- lin somatic hypermutation (SHM), and a light zone (LZ) where B cells are selected based on their af nity for the antigen and perform class-switch recombination (CSR). BL appear to derive from DZ B-cells, whereas FL and DLBCL derive from B-cells arrested at various stag- es of the GC-transit. In particular, FL and the germinal center B-cell (GCB)-like subtype of DLBCL resemble LZ B-cells, while activated B-cell (ABC)-like DLBCLs seem to derive from GC cells entering the post-GC plasma-cell differentiation(2).
❯ Mechanisms of genetic lesions in B-cell non-Hodgkin lymphomas
The coding genomes of B-NHL carry genetic aberra- tions including ampli cations, deletions and non-syn-
Riccardo Dalla-Favera
Institute for Cancer Genetics. Columbia University. New York (USA)
onymous point mutations associated with gain- or loss- of-function consequences. In addition, B-NHL display chromosomal translocations and aberrant SHM(1).
B-NHL-associated translocations do not generate fusion genes and chimeric proteins, typical of acute leukemias, but rather lead to the juxtaposition of het- erologous promoters and/or enhancers to an onco- gene, leading to its dysregulated or ectopic expres- sion. Although the immunoglobulin (Ig) loci represent the most frequently targeted sequences, they can be replaced by a variety of regulatory regions in so called “promiscuous translocations”. B-NHL-associated translocations can be generated by: i) mistakes of the recombination-activating gene (RAG)-mediated V(D) J recombination process –e.g., the t(14;18) transloca- tions involving IGH and BCL2 in FL–; ii) errors in the acti- vation-induced cytidine deaminase (AID)-dependent CSR process (Ig-MYC translocations in sporadic BL); iii) by-products of the AID-mediated SHM mechanism (immunoglobulin-MYC translocations in endemic BL).
Aberrant somatic hypermutation (ASHM) is predom- inantly associated with DLBCL, and appears to derive from the aberrant targeting of multiple non-immuno- globulin loci by the SHM mechanism(3). Multiple muta- tional events targeting > 10% of the transcribed genes can be found in > 50% of DLBCL cases(3). In the case of MYC, a signi cant number of amino-acid substitutions have proven to carry functional consequences in ac- tivating its oncogenic potential(3). However, a compre- hensive understanding of the functional consequenc- es of ASHM is still lacking.
❯ Burkitt lymphoma
Burkitt lymphomas include sporadic (sBL), endemic (eBL) and HIV-associated (HIV-BL) forms(4). All eBL and one third of sBL and HIV-BL cases are infected by the
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LIX Congreso Nacional SEHH-XXXIII Congreso Nacional SETH / Programa Educacional