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M.C.J. Ma et al.
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Figure 5. Subtype-specific patterns of BAF complex mutations. (A) An oncoplot shows the frequency of genetic alterations in genes that encode components of the BAF complex. (B) A schematic of the BAF complex shows recurrently mutated genes, ARID1A, SMARCA4 and BCL7A, and the BCL11A gene that is targeted by 2p15 DNA copy number gains. (C-E) Lollipop plots show the distribution of mutations in the BAF components ARID1A (C), SMARCA4 (D), and BCL7A (E). (F) A heatplot shows the location of chromosome 2p DNA copy number gains (red) ordered from highest DNA copy number (top) to lowest (bottom, copy number = 2.2). The BCL11A gene is in the peak focal copy gain. BL: Burkitt lymphoma; DLBCL: diffuse large B-cell lymphoma; FL: follicular lymphoma; MCL: mantle cell lymphoma.
in epigenetic and transcriptional control of gene expression are known to be a hallmark of FL52 and we observed that 96% of FL tumors possessed mutations in one or more of the genes in this category. However, mutations within these genes were also observed in the majority of BL, DLBCL and MCL tumors, highlighting the conservation of this functional hallmark across B-NHL subtypes. There are subtype-specific patterns of chromatin-modifying gene alterations, such as those that we highlighted for BAF com- plex mutations, but we suggest that the genetic deregula- tion of epigenetic and transcriptional control of gene expression should be considered a general hallmark of B- NHL. In addition, we suggest that the deregulation of the ubiquitin proteasome system is a hallmark of B-NHL that requires further investigation. Mutations in genes such as KLHL637 and UBR539 have recently been shown to play an important role in B-cell lymphoma, while the roles of other frequently mutated genes such as DTX1 and SOCS1 have not yet been functionally dissected. Furthermore, while the nature of AID-driven mutations in genes such as DTX1 and SOCS1 remain to be defined, other genes that are recur- rently mutated by AID such as BCL7A53 and linker histone genes54 have been shown to play driving roles in lym- phomagenesis. Genetic deregulation of the ubiquitin pro- teasome system has the potential to influence the activity or abundance of a range of substrate proteins, and repre- sents a current gap in our knowledge of B-NHL etiology.
The role of cooperative interactions between co-occur- ring genetic alterations is also an emerging field that requires further investigation. These interactions are not uncommon in cancer,55 and have been recently highlighted in DLBCL,3,4 but our data show that they are pervasive and characteristic features of the B-NHL genetic landscape. Cooperation between co-associated genetic alterations identified in this study requires formal validation in cell lines and/or animal models. However, there are many instances in which co-occurring genetic alterations that we observed have already been shown to cooperate in lym- phomagenesis. In addition to the aforementioned example of MYD88 and CD79B mutations, transgenic mouse mod- els of Ezh2 activating mutations or conditional deletion of Crebbp or Kmt2d have shown that these events are not alone sufficient for lymphomagenesis.56-61 We and others have observed a co-association between mutation of these genes and BCL2 translocations,14,62 and the addition of a Bcl2 transgene to these murine models indeed promoted lym- phoma at a significantly higher rate than that observed with the Bcl2 transgene alone.56-61 These genetic alterations are therefore significantly more lymphomagenic in combina- tion than they are alone, which provides proof of principle that a cooperative relationship exists between these co- occurring genetic alterations. Future studies focusing on other co-occurring mutations, such as MYC translocation and SMARCA4 mutation in BL, CREBBP and KMT2D
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haematologica | 2022; 107(3)