Page 19 - Programa Educacional Congres SEHH-SETH 2017

tyl-transferases EP300 and/or CREBBP in about 40% of DLBCL and of the histone methyltransferase MLL2 (~ 30% of cases)(5,9). These alterations consistently tar- get only one allele whereas the other remains intact, suggesting a haploinsuf cient tumor suppressor role of these genes, as recently shown in mouse models(12,13). These lesions favor lymphomagenesis by reprogram- ming the cancer epigenome. Inactivation of CREBBP and/or EP300 has been shown to hamper acetylation- mediated activation of the TP53 tumor suppressor and inactivation of the BCL6 proto-oncogene, thus contrib- uting to lymphomagenesis(9,13). Of note, these lesions may occur early during lymphomagenesis as suggest- ed by their presence in common cell precursors before their divergent progression toward DLBCL or FL(7).
Immune escape may be caused in over 60% of DLBCL cases due to lacking cell-surface expression of the MHC class-I complex, which is necessary for the recognition by cytotoxic T-cells (CTL)(14). This defect is due to inactivation of the gene encoding β-2 micro- globulin (B2M), inactivation of the genes encoding HLA-A, HLA-B and HLA-C and defective transport of B2M or HLA-I molecules on the cell surface by presently unknown mechanisms(14). Interestingly, loss of B2M and therefore inability to express HLA-I on the cell surface, is one of the events recurrently associated with the pro- gression of FL toward DLBCL(7).
GCB-DLBCL. Chromosomal translocations involving MYC and BCL2, analogous to the ones that charac- terize BL and FL, are detected in ~ 10% and ~ 40% of GCB-DLBCL, respectively. The co-occurrence of lesions affecting MYC and BCL2 genes is associated with poor prognosis. The following 3 programs appear to be af- fected with some speci city in GCB-DLBCL. Mutations of the EZH2 gene are found in about 20% of GCB-DLBCL and result in a gain-of-function phenotype(15).The EZH2 gene encodes a methyltransferase involved in the transcriptional repression of CDKN1A, PRDM1 and IRF4, suggesting a role in promoting proliferation and im- pairing differentiation(15). Several chemokines and their receptors, including S1PR2 and P2RY8, are involved in modulating the cell migrations occurring in the GC. Approximately 30% of GCB-DLBCL and a fraction of BL have been shown to carry mutations (S1PR2, GNA13, ARHGEF1 and P2RY8 genes) inactivating the Gα13- dependent pathway, which control the con nement
of B-cells within the GC, thus providing an explanation for the ability of GCB-DLBCL cells to leave their tissue of origin and travel to distant sites(16). Finally, the HVEM re- ceptor (TNFRSF14) gene is mutationally inactivated in GCB-DLBCL, leading to a tumor-supportive microenvi- ronment marked by exacerbated lymphoid stroma ac- tivation and increased recruitment of T follicular helper cells.These changes result from the disruption of inhibi- tory cell-cell interactions between the HVEM and BTLA (B and T lymphocyte attenuator) receptors(17).
ABC-DLBCL. ABC-DLBCLs are dependent upon NF-κB activation as demonstrated by their death upon NF-κB inhibition in vitro(18). A variety of genetic alterations con- verge on the activation of the NF-κB transcription com- plex in ABC-DLBCL(1): i) mutations (20% of cases) in the CD79A/B genes that encode components of the BCR complex, contribute to chronic BCR signaling; ii) activat- ing mutations targeting the CARD11 gene in ~ 10% of ABC-DLBCL lead to hyper-responsiveness of the signal transduction complex CARD11-BCL10-MALT1 to activate NF-κB; iii) mutations (35% of cases) of the MYD88 gene, encoding an adaptor protein that promotes the TLR- and IL1R-mediated activation of IL-1R-associated kinase 2 (IRAK2) and NF-κB; iv) the TNFAIP3 gene, encoding A20, a key negative modulator of the NF-κB pathway, is genetically inactivated in 30% of ABC-DLBCL, thus pre- venting termination of NF-κB responses. Two mecha- nisms, that are largely mutually exclusive, block termi- nal B cell differentiation by converging on the negative regulation of the plasma-cell master regulator PRDM1/ BLIMP1(19,20): i) bi-allelic inactivation of the PRDM1 gene is observed in about 30% of ABC-DLBCL cases; ii) alter- natively, BCL6 dysregulation by chromosomal transloca- tions, that are more frequent in ABC-DLBCL than in GCB- DLBCL, also leads to constitutive repression of PRDM1 by BCL6.This repression of PRDM1 may be even more com- mon in DLBCL cases considering the variety of genetic lesions that have been shown to affect BCL6 expres- sion and activity(8). Finally, ~ 25% of ABC-DLBCL display gain-of-function alterations of SPIB, a transcription factor that can form a complex with IRF4 and contributes to PRDM1 inactivation by directly repressing its transcrip- tion. PRDM1 genetic inactivation in GC B-cells in mice leads to ABC-DLBCL development. These tumors display constitutive NF-κB activation, demonstrating the require- ment of both pathways for ABC-DLBCL pathogenesis.
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LIX Congreso Nacional SEHH-XXXIII Congreso Nacional SETH / Programa Educacional