SNOMEDCT: 118617000, 397400006, 77381001; ICD10CM: C83.7, C83.70; ICD9CM: 200.2; ORPHA: 543; DO: 8584;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8q24.21 | Burkitt lymphoma, somatic | 113970 | 3 | MYC | 190080 |
A number sign (#) is used with this entry because of evidence that Burkitt lymphoma can be caused by somatic mutation in the MYC gene (190080) in addition to translocations involving the MYC gene and immunoglobulin genes (see 147220).
Burkitt lymphoma is a rare, aggressive B-cell lymphoma that accounts for 30 to 50% of lymphomas in children but only 1 to 2% of lymphomas in adults (Harris and Horning, 2006). It results from chromosomal translocations that involve the MYC gene (190080) and either the lambda or the kappa light chain immunoglobulin genes (147220, 147200). Burkitt lymphoma is causally related to the Epstein-Barr virus (EBV), although the pathogenetic mechanisms are not clear.
Anderson et al. (1986) described 2 sisters in an American family who died of Burkitt lymphoma at ages 11 and 22 years. The mother and 2 healthy brothers had abnormality of lymphocyte subsets. An inherited disturbance of lymphocytes was thought to underlie the familial aggregation for Burkitt lymphoma.
Most BL cell lines show a specific translocation involving chromosome 8 (breakpoint at 8q24) and either 2, 14 or 22. The type of immunoglobulins produced by this B-cell tumor correlates with the type of translocation (Lenoir et al., 1982): those with the 8;2 translocation produce predominantly kappa light chains; those with the 8;22 translocation produce lambda light chains; those with the 8;14 translocation produce immunoglobulins with both types of light chains. Furthermore, the kappa and lambda light chains map to the regions of 2p and 22q, respectively, that are involved in the breakpoint creating the translocations; in the 8;14 translocations, the breakpoint is the 14q32 band where the genes for immunoglobulin heavy chains map (Kirsch et al., 1982).
Klein (1981) suggested that the consistent involvement of 8q24 may indicate that activation of an onc gene underlies this tumor. In this connection, it is noteworthy that the mos onc gene (190060) has been assigned to chromosome 8; the regional localization will be of interest, as well as information on mos DNA sequences in BL. In Burkitt lymphoma of the t(8;22) type, the breakpoint in chromosome 22 is proximal to the lambda immunoglobulin constant gene cluster (147220), whereas in the translocation t(9;22) of CML (608232) it is distal (Emanuel et al., 1984). Burkitt lymphoma and related neoplasms have their analog in murine plasmacytomas (also referred to as myelomas) in which a specific translocation occurs between mouse chromosome 15 and either mouse chromosome 12 (which in the mouse carries the heavy chain genes) or mouse chromosome 6 (which carries the kappa light chain genes). Calame et al. (1982) identified a region of DNA on mouse chromosome 15 that is commonly rearranged in transformed mouse lymphocytes.
Haluska et al. (1987) presented evidence that the t(8;14) chromosome translocation of the Burkitt lymphoma cell line Daudi occurred during immunoglobulin gene rearrangement and involved the heavy chain diversity region (146910). They suggested that the translocation resulted from a recombinase error.
Neri et al. (1988) showed that the endemic, sporadic, and AIDS-associated forms of Burkitt lymphoma carrying t(8;14) chromosomal translocations display different breakpoints within the immunoglobulin heavy-chain locus. Cloning and sequencing of the t(8;14) chromosomal junctions from 2 endemic BL cell lines and 1 endemic BL biopsy sample showed that the recombinations did not involve IGH-specific recombination signals on chromosome 14 or homologous sequences on chromosome 8. Thus, these events probably were not mediated by the same mechanisms or enzymes as in IGH rearrangement.
EBV is stably maintained and partially expressed in Burkitt lymphoma and in nasopharyngeal carcinoma. Latently infected cells usually contain multiple episomal copies of nonintegrated viral DNA. In 2 Burkitt cell lines, Henderson et al. (1983) showed that EBV was also integrated into a chromosome, but different chromosomes (chromosomes 1 and 4). The persistence of EBV in latently infected cells over years of active cell replication may be explained by integration. It is noteworthy that the site of integration is removed from those involved in the translocation. 'The simplest model to explain EBV association with Burkitt tumors is that EBV induces B-cell proliferation and thereby provides enhanced opportunity for chromosomal translocation and malignant degeneration' (Henderson et al., 1983).
Haluska et al. (1987) suggested the following scenario for African Burkitt lymphoma: EBV is a polyclonal activator of B lymphocytes, and infection of normal B cells in vitro by EBV is associated with immortalization. In regions of equatorial Africa where Burkitt lymphoma is endemic, 80% of children demonstrate evidence of EBV infection. Malaria is also hyperendemic in the area and causes immunosuppression. Polyclonal B-lymphocyte proliferation therefore proceeds unchecked in the absence of T-cell suppression, probably enlarging the population of cells susceptible to translocation. Translocation involving the IgH locus (147100) leads to deregulation of the MYC oncogene. In Europe and North America, childhood EBV infection is less frequent, as is malaria. Burkitt lymphoma appears to occur in mature B cells following antigenic stimulation and during isotype switching.
EBV is associated with nearly all BL in Africa, but is only associated with 20% or fewer cases of sporadic BL worldwide. All BL tumors share the translocation of Ig and MYC genes. Following EBV infection of primary B lymphocytes, EBV-determined nuclear antigens (EBNA) appear, first EBNA2, a transcriptional activator of specific viral and cellular genes, particularly in the NOTCH (see 190198) pathway, then EBNA-leader protein and the other EBNAs. Latent membrane proteins are then expressed, including LMP1, which interacts with TRAFs (see 601896), and the abundant EBERs (EBV-encoded small nonpolyadenylated RNAs), which are transcribed by RNA polymerase III (see 606007).
Komano et al. (1998) showed that EBV-negative BL clones infected with recombinant virus regained the ability of the EBV-positive parent clone to grow on soft agar and to be tumorigenic in immunodeficient SCID mice. In addition, the EBV-positive lines expressed higher levels of BCL2 (151430) and were more resistant to apoptosis than EBV-negative cells. Transfection of EBNA1, which is required for replication of the viral episome, into EBV-negative BL lines did not restore the malignant phenotype or apoptosis resistance. Komano et al. (1998) concluded that persistence of EBV is required for BL malignancy and apoptosis resistance.
Komano et al. (1999) showed that transfection of EBER1 and EBER2 into EBV-negative BL lines restored the capacity for malignancy and apoptosis resistance. They suggested that EBV infection upregulates BCL2 expression, protects cells from MYC-induced apoptosis, and permits MYC to exert its oncogenic functions.
Kitagawa et al. (2000) found that the EBERs of EBV-positive Akata and Mutu BL cell lines activated higher levels of IL10 (124092) expression than EBV-negative cells and enabled growth of BL cells. RT-PCR analysis revealed that EBV-positive but not EBV-negative BL tumors expressed both EBERs and IL10, suggesting that BL cells use IL10 as an autocrine growth factor. IL10 enhanced the growth of EBV-negative cells in culture, but transfection of IL10 into such cells did not confer tumorigenicity in SCID mice. Kitagawa et al. (2000) proposed that RNA molecules can regulate cell growth.
The EBV growth-transforming (Latency III) program of gene expression is extinguished in tumor cells, and only a single viral protein, EBNA1, is expressed via the alternative Latency I program. It was not known if BL arises from a B-cell subset in which EBV naturally adopts a Latency I infection or if selection of a clone with limited antigen expression from an EBV-transformed Latency III progenitor pool occurs. Kelly et al. (2002) identified a subset of BL tumors in which the Latency III-associated EBNA promoter Wp is active and most EBNAs are expressed, but where a gene deletion has specifically abrogated the expression of EBNA2. Kelly et al. (2002) concluded that BL can be selected from a Latency III progenitor and that the principal selection pressure is for downregulation of the c-Myc antagonist EBNA2.
Schmitz et al. (2012) used high-throughput RNA sequencing and RNA interference screening to discover essential regulatory pathways in BL that cooperate with MYC (190080), the defining oncogene of this cancer. In 70% of sporadic BL cases, mutations affecting the transcription factor TCF3 (E2A; 147141) or its negative regulator ID3 (600277) fostered TCF3 dependency. TCF3 activated the prosurvival phosphatidylinositol-3OH kinase pathway in BL, in part by augmenting tonic B-cell receptor signaling. In 38% of sporadic BL cases, oncogenic CCND3 (123834) mutations produced highly stable cyclin D3 isoforms that drive cell cycle progression.
Varano et al. (2017) studied the effects of B-cell antigen receptor (see 107265) ablation on MYC-driven mouse B-cell lymphomas and compared them with observations in human Burkitt lymphoma. Whereas BCR ablation does not, per se, significantly affect lymphoma growth, BCR-negative (BCR-) tumor cells rapidly disappear in the presence of their BCR-expressing (BCR+) counterparts in vitro and in vivo. This requires neither cellular contact nor factors released by BCR+ tumor cells. Instead, BCR loss induces the rewiring of central carbon metabolism, increasing the sensitivity of receptor-less lymphoma cells to nutrient restriction. The BCR attenuates glycogen synthase kinase-3-beta (GSK3-beta; 605004) activity to support MYC-controlled gene expression. BCR- tumor cells exhibit increased GSK3-beta activity and are rescued from their competitive growth disadvantage by GSK3-beta inhibition. BCR- lymphoma variants that restore competitive fitness normalize GSK3-beta activity after constitutive activation of the MAPK (see 176948) pathway, commonly through Ras (see 190020) mutations. Similarly, in Burkitt lymphoma, activating RAS mutations may propagate immunoglobulin-crippled tumor cells, which usually represent a minority of the tumor bulk. Thus, while BCR expression enhances lymphoma cell fitness, BCR-targeted therapies may profit from combinations with drugs targeting BCR- tumor cells.
Bhatia et al. (1993) screened the MYC gene in a panel of 57 BL biopsies and cell lines and found that 65% had at least 1 amino acid substitution (see, e.g., 190080.0001-190080.0004). The mutations were apparently homozygous in all BL cell lines tested and in 2 tumor biopsies, implying that the mutations often occur before MYC/immunoglobulin translocation in BL.
Harris and Horning (2006) reviewed the work of Hummel et al. (2006) and Dave et al. (2006), which reported the use of gene expression microarray technology to improve the accuracy of the diagnosis of Burkitt lymphoma. Both studies concluded that the gene expression profiling of cases classified as Burkitt lymphoma by expert pathologists identifies a characteristic genetic signature that clearly distinguishes this tumor from cases of diffuse large B-cell lymphoma. Burkitt lymphoma is rapidly fatal if untreated, but it is curable with intensive chemotherapy, typically, high doses of cyclophosphamide and antimetabolites, as well as intrathecal chemotherapy. The treatment that is appropriate for diffuse large B-cell lymphoma is not curative for Burkitt lymphoma.
Using whole-genome, whole-exome, and transcriptome sequencing of 4 prototypical Burkitt lymphomas with immunoglobulin gene (IG)-MYC translocation, Richter et al. (2012) identified 7 recurrently mutated genes. One of these genes, ID3, mapped to a region of focal homozygous loss in Burkitt lymphoma. In an extended cohort, 36 of 53 molecularly defined Burkitt lymphomas (68%) carried potentially damaging mutations of ID3. These were strongly enriched at somatic hypermutation motifs. Only 6 of 47 other B-cell lymphomas with the IG-MYC translocation (13%) carried ID3 mutations. Richter et al. (2012) concluded that their findings suggested that cooperation between ID3 inactivation and IG-MYC translocation is a hallmark of Burkitt lymphomagenesis.
Love et al. (2012) described the first completely sequenced genome from a Burkitt lymphoma tumor and germline DNA from the same affected individual, and further sequenced the exomes of 59 Burkitt lymphoma tumors and compared them to sequenced exomes from 94 diffuse large B-cell lymphoma tumors. Love et al. (2012) identified 70 genes that were recurrently mutated in Burkitt lymphomas, including ID3, GNA13 (604406), RET (164761), PIK3R1 (171833), and the SWI/SNF genes ARID1A (603024) and SMARCA4 (603254). Love et al. (2012) stated that their data implicate a number of genes in cancer for the first time, including CCT6B (610730), SALL3 (605079), FTCD (606806), and PC (608786). ID3 mutations occurred in 34% of Burkitt lymphomas and not in diffuse large B-cell lymphomas (DLBCLs). Love et al. (2012) showed experimentally that ID3 mutations promote cell cycle progression and proliferation.
Denis Parsons Burkitt, who died in 1993 at the age of 82, was famed for the distinctive lymphoma he described and for the dietary fiber hypothesis he developed and espoused (Heaton, 1993).
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