Table 3.
Frequency of some mutated genes in EBV-positive BL.
| Gene | Frequency (sample size) | Name | Description | Compensation for EBV |
|---|---|---|---|---|
| IGLL5 a | 97% (n = 39)1 | Immunoglobulin lambda-like polypeptide 5 | Located within the immunoglobulin lambda locus but does not require somatic rearrangement for expression. | Mutations in IGLL5 could compensate since IGLL5 is regulated by EBV (Zhou et al., 2015) |
| DDX3X | 35% (n = 20)2
40% (n = 30)3 62% (n = 94)4 82% (n = 39)1 |
DEAD (Asp–Glu–Ala–Asp) box polypeptide 3, X-linked | ATP-dependent RNA helicase. | Unknown |
| IKZF3 | 44% (n = 39)1 | IKAROS Family Zinc Finger 3 | TF that plays an essential role in regulation of B-cell differentiation, proliferation, and maturation to an effector state. | Mutations in IKZF3 could compensate since IKZF3 is regulated by EBV (Zhou et al., 2015) |
| FOXO1 | 7% (n = 30)3
30% (n = 94)4 56% (n = 39)1 |
Forkhead box O1 | Key TF regulated by the PI3K/AKT pathway. Loss of function mutations may have a role in cell growth or escape from apoptosis. | Unknown |
| SIN3A | 18% (n = 94)4
41% (n = 39)1 |
SIN3 transcription regulator family member A | Acts as a transcriptional repressor. Corepressor for REST. Interacts with MXI1 to repress MYC responsive genes and antagonize MYC oncogenic activities. | Mutations in SIN3A could compensate for EBNA3C through interaction with Sin3A (Jiang et al., 2014) |
| S1PR2 | 28% (n = 39)1 | Sphingosine-1-Phosphate Receptor 2 | Receptor for the lysosphingolipid sphingosine 1-phosphate (S1P). S1P elicits diverse physiological effects on most types of cells and tissues. | Mutations in S1PR2 could compensate for LMP1 which regulates S1PR2 (Vockerodt et al., 2019) |
| FBXO11 | 13% (n = 30)3
18% (n = 94)4 36% (n = 39)1 |
F-box protein 11 | Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex. Major target is BCL6. Loss of function mutations. | Mutations in FBXO11 could compensate for EBNA3C through BCL6 interaction (Pei et al., 2017) |
| CREBBP | 21% (n = 39)1 | CREB Binding Protein | Acetylates histones, giving a specific tag for transcriptional activation. Also acetylates non-histone proteins, including DDX21, FBL, IRF2, MAFG, NCOA3, POLR1E/PAF53, and FOXO1. | Mutations in CREBBP could compensate for EBNA2 through direct interaction with CBP to activate the LMP1 promoter (L. Wang et al., 2000) |
| TP53 b | 15% (n = 20)2
17% (n = 30)3 22% (n = 94)4 33% (n = 12)5 15% (n = 39)1 |
Tumor protein p53 | Encodes p53, a tumor suppressor that binds to DNA and regulates gene expression. Can activate DNA repair proteins when DNA is damaged and arrest the cell cycle at the G1/S checkpoint, or initiate apoptosis if DNA damage is irreversible. Mutations are loss of function. | Mutations in TP53 could compensate for EBV’s genes that block apoptosis |
| IRF8 a | 18% (n = 39)1 | Interferon Regulatory Factor 8 | Plays a role as a transcriptional activator or repressor. Plays a negative regulatory role in immune cells. | Mutations in IRF8 could compensate for EBNA3C through its interaction with IRF8 (Banerjee et al., 2013) |
| CCND3 a b | 5% (n = 20)2
13% (n = 30)3 10% (n = 94)4 31% (n = 39)1 |
Cyclin D3 | A regulator of progression through G1 phase during cell cycle. Loss of C terminal domain leads to constitutive activation. | Mutations in CCND3 could compensate for unregulated cell cycle progression |
| RHOA a | 20% (n = 20)2
13% (n = 30)3 10% (n = 94)4 15% (n = 39)1 |
Ras homolog family member A | Small GTpase protein in the Rho family. Regulation of signal transduction between membrane receptors and focal adhesion molecules. Likely loss of function mutations. | Unknown |
| USP7 b | 4% (n = 94)4 | Ubiquitin Specific Peptidase 7 | USP7 deubiquitinates target proteins such as p53 and regulates their activities by counteracting opposing ubiquitin ligase activity. | Mutations in USP7 could compensate for EBNA1 through its interaction (Holowaty and Frappier, 2004) |
| Mutations involved in epigenetic regulation b | ||||
| HIST1H2BK | 49% (n = 39)1 | Histone H2B | Unknown | |
| HIST1H3H | 44% (n = 39)1 | Histone H3.1 | Unknown | |
| HIST1H1E | 11% (n = 94)4
64% (n = 39)1 |
Histone H1.4 | Unknown | |
| HIST1H1C | 28% (n = 39)1 | Histone H1.2 | Unknown | |
| CHD8 | 10% (n = 94)4
26% (n = 39)1 |
Chromodomain Helicase DNA Binding Protein 8 | DNA helicase that acts as a chromatin remodeling factor and regulates transcription. | Unknown |
| KMT2D a | 14% (n = 94)4
5% (n = 39)1 |
Histone-lysine N-methyltransferase 2D | Colocalizes with TFs on transcriptional enhancers. Plays critical roles in regulating cell fate transition, metabolism, and tumor suppression. | Unknown |
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).
c
Significantly more frequently mutated in EBV-negative BL (Grande et al., 2019).
Annotations in acronym or abbreviated form are: TF, transcription factor.
1. Panea et al., 2019; 2. Abate et al., 2015; 3. Kaymaz et al., 2017; 4. Grande et al., 2019; 5. Giulino-Roth et al., 2012.