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Non-Hodgkin Lymphoma
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
NGS studies have shown that the GCB cell DLBCL is often associated with aberrations in genes involved in epigenetic pathways (MFHAS1, XP01, MYC, CDKN2A/B, FOXO1, TP53, GNA13 and BCL2), and the apoptosis/cell cycle pathway (EZH2, KMT2D, EP300, MEF2B and CREBBP); in contrast, the ABC subtype is often characterized by the preferential aberrant activation of the NF-κb pathway (TNFAIP3, MYD88, PIM1, CARD11, IRF4 and PRDM1), whilst both the ABC subtype and PMBL are associated with the JAK/STAT pathway (JAK1, JAK3, STAT3, STAT5B, STAT6 and SOCS1), apoptosis/cell cycle and the immune modulatory pathway (CIITA, B2M, TNFRSF14 and CD58). The presence of CD274 (PD-L1) and PDCD1LG2 (PD-L2) locus as a recurrent translocation partner for IGH, PIM1 and TP63 in the non-GCB DLBCL subtypes, suggestive of the potential use of immune checkpoint inhibitors in the treatment of these poor-risk patients, has also been shown. Other important signalling pathways for both B-cell and T-cell lymphomas include NOTCH (NOTCH1, NOTCH2 and UBR5), MAPK (BRAF), BCR (CD79A/B, ITPKB, TCF3 and ID3), PI3K/MTOR and the focal adhesion pathway (GNA13, RHOA) (Figure 11.11).
BCL6 as a therapeutic target for lymphoma
Published in Expert Opinion on Therapeutic Targets, 2018
Rebecca J Leeman-Neill, Govind Bhagat
Mutations in proteins that regulate BCL6 expression have been observed in B-NHL. For example, histone/protein lysine acetyltransferases CREBBP and EP300, as well as MEF2B, a transcriptional activator, are mutated in subsets of FL and DLBCL, resulting in deregulated activity of BCL6 in vitro [37,38]. Recent in vivo studies have functionally verified CREBBP’s function as a tumor suppressor in murine models of lymphoma, with loss of function CREBBP mutations resulting in BCL6 deregulation [39,40]. A subset of DLBCLs also harbor mutations in FBXO11, a ubiquitin ligase, which results in decreased proteosomal degradation and a longer half-life of BCL6 [41]. Additionally, studies in an animal model have implicated deregulation of HDAC9 and resultant changes in acetylation of BCL6 in lymphomagenesis. Finally, CpG hypermethylation of exon 1 of BCL6, resulting in inhibition of CTCF mediated regulation and increased expression of BCL6, has been observed in Raji (BL) cells [42].
Identifying aggressive subsets within diffuse large B-cell lymphoma: implications for treatment approach
Published in Expert Review of Anticancer Therapy, 2022
Timothy J Voorhees, Narendranath Epperla
More recently, Hodson and colleagues from the Hematologic Malignancy Research Network reported their result of WES in 928 DLBCL cases [31]. Five genetic subtypes were described with the following terms: MYD88, BCL2, SOCS1/SK1, TET2/SK1, and NOTCH2 as well as an unclassifiable group. The MYD88 cluster was characterized by mutations in MYD88L265P, PIM1, CD79B and ETV6, which is similar to the MCD cluster from Staudt and colleagues. The BCL2 cluster had frequent mutations in EZH2, BCL2, CREBBP, TNFRSF14, KMT2D, and MEF2B, similar to both the EZB and C3 clusters as previously described. The SOCS1/SK1 cluster had mutations in SOC1, CD83, SGK1, NFKBIA, HIST1H1E, and STAT3. The TET2/SK1 cluster was characterized by mutations in TET2, SGK1, KLHL6, ZFP36L1, BRAF, MAP2K1, and KRAS. Finally, the NOTCH2 cluster had mutations in NOTCH2, BCL10, TNFAIP3, CCND3, SPEN, TMEM30A FAS, CD70, and BCL6 fusions, similar to both BN2 and C1 clusters described above. Even in this study, only marginal impact on OS was observed between the clusters with the MYD88 cluster having the worst OS and the BCL2 cluster having the best OS. Interestingly, TP53 mutations were observed in similar frequency across the subtypes, but within each subtype, TP53 mutations had a differential impact on OS. The largest impact was observed in the MYD88 cluster in which OS was remarkably worse with concurrent TP53 mutation. Fortunately, TP53 mutations were only observed in 6 of 80 cases in the MYD88 cluster, though this limits its wide scale use in prognostication.
Enhancing prognostication and personalizing treatment of extranodal marginal zone lymphoma
Published in Expert Review of Hematology, 2023
Juan Pablo Alderuccio, Izidore S. Lossos
Compared to other B-cell lymphomas, determining mutational profile in EMZL has been problematic due to frequently small pathological sample sizes limiting comprehensive genomic interrogation. Several studies attempted to assess mutations present in this disease with most studies including a relatively small number of specimens. There are four main recurrent chromosomal translocations implicating specific genes and pathways in the pathogenesis of EMZL: BCL10::IGH at t(1;14)(p22;q32), API2:MLT at t(11;18)(q21;21), MALT1:IGH at t(14;18)(q32;q21), and FOXP1:IGH at t(3;14)(p14.1;32) [38–43]. Across all extranodal sites, the most common mutations occur in TNFAP3 (29%), CREBBP (22%), KMT2C (19%), TET2 (17%), SPEN (17%), and KMT2D (15%) genes [10,34]. However, during the 2022 American Society of Hematology annual meeting, our group presented the largest whole-exome sequencing analysis in EMZL (n = 225) describing mutations in IGLL5 (22%) as the most common alteration across all extranodal sites [44]. We also observed mutations in PRDM2 (11%) and NCOR1 (10%) which were not previously reported. This analysis described a significant enrichment of aberrations in genes involved in NOTCH signaling, DNA repair, cancer-associated sustaining of proliferative signaling, cancer-associated histone methylation, and positive regulation of transcription. EMZL demonstrates distinct genomic alterations according to the primary extranodal site of disease but commonly affects signaling pathways central to the homeostasis of normal marginal zone B cells including NF-ĸB, BCR, NOTCH, MEF2B, and NFAT [9,36]. Genomic profile does not seem to be associated with stage of disease [10,45].