Table 2.
Frequency of some AID off-target genes1 mutated in EBV-positive BL.
| Gene | Frequency (sample size) | Name | Description † | Compensation for EBV † |
|---|---|---|---|---|
| BACH2 | 97% (n = 39)2 | BTB Domain And CNC Homolog 2 | – | – |
| MYC * | 50% (n = 20)3
60% (n = 30)4 61% (n = 94)5 97% (n = 39)2 |
v-myc myelocytomatosis viral oncogene homolog | TF that drives cell-cycle progression and transformation. Translocation of MYC to one of three immunoglobulin loci causes constitutive expression. | Mutations in MYC could compensate for EBV’s genes that sustain proliferation |
| BCL6 a | 56% (n = 39)2 | BCL6 Transcription Repressor | Transcriptional repressor. In GC B-cells, represses genes that function in differentiation, inflammation, apoptosis and cell cycle control, also autoregulates its transcriptional expression and up-regulates, indirectly, the expression of some genes important for GC reactions, such as AID, through the repression of microRNAs expression, like miR155. | Mutations in BCL6 could compensate for EBNA3C through its direct interaction with this protein (Pei et al., 2017) |
| BTG2 | 51% (n = 39)2 | BTG Anti-Proliferation Factor 2 | – | – |
| TCL1A | 41% (n = 39)2 | T Cell Leukemia/Lymphoma 1A | – | – |
| ID3 | 30% (n = 20)3
33% (n = 30)4 33% (n = 94)5 62% (n = 39)2 |
Inhibitor of DNA binding 3 | HLH protein lacking DNA-binding domain. Functions as a negative regulator of TCF3, inhibiting transcription. Mutations are inactivating which decrease TCF3 interaction. | See TCF3 |
| DNMT1 | 36% (n = 39)2 | DNA Methyltransferase 1 | Methylates CpG residues. Preferentially methylates hemimethylated DNA. | Mutations in DMNT1 could compensate for its interaction with LMP1 and LMP2A (Tsai et al., 2006; Hino et al., 2009). |
| MCL1 | 33% (n = 39)2 | MCL1 Apoptosis Regulator, BCL2 Family Member | – | – |
| ARID1A | 25% (n = 20)3
13% (n = 30)4 45% (n = 94)5 46% (n = 39)2 |
AT rich interactive domain 1A | – | – |
| ETS1 | 13% (n = 94)5
51% (n = 39)2 |
ETS Proto-Oncogene 1, Transcription Factor | – | – |
| DTX1 | 31% (n = 39)2 | Deltex E3 Ubiquitin Ligase 1 | – | – |
| PVT1 b | 28% (n = 39)2 | Pvt1 Oncogene | – | – |
| GNA13 | 17% (n = 30)4
17% (n = 94)5 46% (n = 39)2 |
Guanine nucleotide binding protein, alpha 13 |
– | – |
| BCL7A | 13% (n = 30)4
9% (n = 94)5 56% (n = 39)2 |
B-cell CLL/lymphoma 7A | – | – |
| ZFP36L1 | 26% (n = 39)2 | ZFP36 Ring Finger Protein Like 1 | – | – |
| TMSB4X | 23% (n = 39)2 | Thymosin Beta 4 X-Linked | – | – |
| CXCR4 | 21% (n = 39)2 | C-X-C Motif Chemokine Receptor 4 | – | – |
| TFAP4 | 17% (n = 30)4
10% (n = 94)5 18% (n = 39)2 |
Transcription Factor AP-4 (activating enhancer binding protein 4) |
– | – |
| TCF3 | 15% (n = 20)3
10% (n = 30)4 6% (n = 94)5 28% (n = 39)2 |
Transcription Factor 3 (E2A immunoglobulin enhancer binding factors E12/E47) |
TF that plays a critical role in lymphocyte development. It has also been shown to directly enhance Notch signaling targets. Mutations lead to gain of function. | Gain of function mutations in TCF3 could compensate for EBNA2, 3A, 3B, 3C and/or LMP2A (Robertson et al., 1996; Gordadze et al., 2001; Portis and Longnecker, 2004; Wang et al., 2016). |
| PTEN | 1% (n = 9)5 | Phosphatase And Tensin Homolog | Functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. | Mutations in PTEN could compensate for the inhibition of PTEN by EBV’s miRNA BART6-3p (Cai et al., 2015) |
*This frequency does not include MYC translocations.
a
Identified dependency factor for BL cell line P3HR1 (Ma et al., 2017).
b
Significantly more frequently mutated in EBV-positive BL (Grande et al., 2019).
†The “Description” and “Compensation for EBV” columns in genes marked with (-) have been intentionally left blank since there is not enough information to interpret their contributions to these tumors.
Annotations in acronym or abbreviated form are: TF, transcription factor; AID, activation-induced cytidine deaminase; HLH, helix-loop-helix; GC, germinal center.
1. Álvarez-Prado et al., 2018; 2. Panea et al., 2019; 3. Abate et al., 2015; 4. Kaymaz et al., 2017; 5. Grande et al., 2019.