Burkitt lymphoma


Burkitt's lymphoma is a cancer of the lymphatic system, particularly B lymphocytes found in the germinal center. It is named after Denis Parsons Burkitt, the Irish surgeon who first described the disease in 1958 while working in equatorial Africa. It is a highly aggressive form of cancer which often, but not always, manifests after a person develops acquired immunodeficiency from infection with Epstein-Barr Virus or Human Immunodeficiency Virus.
The overall cure rate for Burkitt's lymphoma in developed countries is about 90%. Burkitt's lymphoma is uncommon in adults, in whom it has a worse prognosis.

Classification

Burkitt lymphoma can be divided into three main clinical variants: the endemic, the sporadic, and the immunodeficiency-associated variants. By morphology, immunophenotype, and genetics, the variants of Burkitt lymphoma are alike.
  • The endemic variant most commonly occurs in children living in regions where malaria is endemic. Epstein–Barr virus infection is found in nearly all patients. Chronic malaria is believed to reduce resistance to EBV, allowing EBV infection to occur. The disease characteristically involves the jaw or other facial bone, abdomen, cecum, distal ileum, ovaries, kidney, or breast. Less than 10% of cases present with central nervous system involvement, which usually manifest as cranial nerve palsies or spinal cord compression.
  • The sporadic type of Burkitt lymphoma is the most common variant found in places where malaria is not endemic such as North America and parts of Europe. The median onset is 10 years of age, but there are also peaks at ages 40 and 75 years old. Males are 3-4 times more likely to be affected as compared to females. The tumor cells have a similar appearance to those of the classical endemic Burkitt lymphoma. Sporadic type Burkitt lymphomas are less commonly associated with the EBV virus as compared to the endemic variant; with 20-30% of cases being attributed to EBV. The jaw is less commonly involved in this variant. The abdominal region is the most common site of involvement, often at the right lower quadrant. The bone marrow is involved in 30-35% of cases and the central nervous system is involved in approximately 20% of cases.
  • Immunodeficiency-associated Burkitt lymphoma is usually associated with HIV infection, but can also occur in the setting of post-transplant patients. The median age of onset of the immunodeficiency-associated variant is between 40-45 years of age and it is equally prevalent in males and females. It makes up 40% of the HIV associated lymphomas, and it usually occurs in those with normal CD4+ T cell counts. EBV is detected in 25-40% of cases and common areas of involvement include GI tract, lymph nodes and bone marrow with 20-30% of affected people having central nervous system involvement.
Burkitt lymphoma is commonly associated with the infection of B cell lymphocytes with the EBV and in these cases is considered to be one form of the Epstein–Barr virus-associated lymphoproliferative diseases. The endemic variant of Burkitt lymphoma is in almost all cases associated with EBV infection. The fact that some Burkitt lymphoma cases do not involve EBV allows that many cases of the disease are not caused and/or promoted by EBV, i.e. the virus may be an innocent passenger virus in these cases. However, the almost ubiquitous presence of the virus in the endemic variant of Burkitt lymphoma suggests that it contributes to the development and/or progression of this variant. The mutational landscape in Burkitt lymphoma has recently been found to differ between tumors with and without EBV infection, further strengthening the role of the virus in disease origin.

Pathophysiology

Genetics

Almost all cases of Burkitt lymphoma are characterized by dysregulation of the c-myc gene by one of three chromosomal translocations which place the myc gene under the control of an immunoglobulin gene enhancer. The MYC gene is found at 8q24.
  • The most common variant is t, which accounts for about 70 to 80% of cases of cases. This involves c-myc oncogene translocation from chromosome 8 to the Ig heavy chain region of chromosome 14. A variant of this, a three-way translocation, t, has also been identified.
  • Another variant is t. This involves the myc oncogene being translocated from chromosome 8 to the Ig kappa locus on chromosome 2. This type of translocation is seen in 15% of cases of Burkitt lymphoma.
  • A rare variant is t. This type involves myc oncogene translocation from chromosome 8 to the Ig lambda locus on chromosome 22. This type of translocation is involved in about 5% of cases of Burkitt lympohoma.
The c-myc gene found on chromosome 8 is part of the MYC family of genes that serve as regulators of cellular transcription and is associated with Burkitt lymphoma. Expression of the c-myc gene results in the synthesis of transcriptional factors that increase the expression of other genes involved in aerobic glycolysis. Ultimately, an increase in aerobic glycolysis plays a role in providing the necessary energy for cellular growth to occur. The translocation of the c-myc gene to the IGH, IGK, or IGL region moves the gene to a location in the genome near immunoglobulin enhancers which increases the expression of the c-myc gene. Overall, this translocation leads to increased cellular proliferation that is found in Burkitt lymphoma. Point mutations can also be present in the translocated c-myc gene resulting in the expressed c-myc protein being overactive.
Bcl-2 translocations, which are frequently seen in follicular lymphomas and other B-cell Non-Hodgkin Lymphomas, do not occur in Burkitt lymphomas.
One of the above described translocations of MYC is seen in 90% of cases of Burkitt lymphoma, but these oncogenic translocations are not usually sufficient to cause lymphoma; other mutations must also be present. These additional mutations include mutations of the tumor suppressor TP53, which interacts with the tumor suppressor p53. But with TP53 and p53 mutated, apoptosis is blocked, and the oncogenic B-cells are allowed to proliferate unchecked. The tumor suppressors ARF and USP7 are also frequently mutated in Burkitt lymphoma leading to MDM2 inhibition of the tumor suppressor p53 which then leads to enhanced oncogenesis. SIN3A, a regulator of MYC, that acts to inhibit MYC by deacetylating it, is often inactivated in Burkitt lymphoma. Also, sequential mutations of the RNA helicases DDX3X and DDX3Y lead to MYC oncogenesis in Burkitt lymphoma. Early in the pathogenesis process, DDX3X mutations limit translation allowing lymphoma cells to escape MYC induced proteotoxic stress and apoptosis, then later, DDX3Y mutations restore high level protein synthesis and leading to increased proliferation of tumor cells. These sequential DDX3X and DDX3Y mutations are thought to partially explain why Burkitt lymphoma is more common in males as the DDX3Y RNA helicase is only found on the Y chromosome.
Mutations affecting the transcription factor TCF3 and its negative regulator ID3 are found in about 70% of cases of Burkitt lymphoma. These mutations prevent ID3 from binding to and inhibiting TCF3; thus the hyperactive TCF3 then activates B cell receptors which activate PI3K and mTOR, as well as Ig heavy and light chain genes, which contribute to oncogenesis. TCF3 and ID3 mutations lead to continuously active B-cell receptors, explaining the high level of proliferation seen in Burkitt lymphoma. Mutations of ID3 and TCF3 are rarely seen in other aggressive B-cell lymphomas; as a result, they can be used to direct further diagnostic workup if identified.
The cell cycle regulators Cyclin D3 and p16 may also be activated and deactivated respectively in Burkitt lymphoma; leading to massive tumor cell proliferation.
Some epigenetic mechanisms have been found to play a role in the pathogenesis of Burkitt lymphoma. FBXO11 is a chromatin regulator. By activating ubiquitin ligase, FBXO11 causes ubiquitination of BCL6 which causes it to be targeted for proteasome degradation. BCL6 normally helps B cells mature in the germinal center and produce antibodies specific to encountered antigens. In Burkitt lymphoma, FBXO11 is deactivated, leading to increased BCL6 activation which then leads to increased proliferation and decreased maturation of germinal center B-cells, thus promoting lymphomagenesis.
EBV associated Burkitts has increased expressional activity of activation-induced cytidine deaminase, which is a mutator, this leads to EBV associated Burkitt lymphomas having more mutations than non-EBV types. Non-EBV subtypes of Burkitt lymphoma more commonly have dysregulation of cyclin D3 and mutated, inactivated p53.

Virology

The complete role of EBV in the pathogenesis of endemic Burkitt lymphoma is not completely elucidated, but it has been shown to cause DNA damage, dysfunction of telomeres, and genome instability. Although the specific pathogenic mechanisms of EBV in Burkitt Lymphoma are unclear, there has been an interest in further elucidating these aspects, particularly with the rise of transcriptomics. BART miRNAs are encoded by the EBV genome and highly expressed in cells infected by EBV. Due to their ability to bind complementary mRNA sequences and thereby prevent gene expression, BART miRNAs assist EBV-infected cells in avoiding detection by the immune system. BART miRNAs thus contribute to EBV-infected cell survival and proliferation. BART miRNAs may prove to be a new therapeutic target or specific biomarker for Burkitt Lymphoma patients. However, there needs to be further research into BART miRNAs interact with intrinsic signaling pathways and contribute to malignancy before any further conclusions can be made.
B cell infection with EBV is latent, and the virus does not undergo replication.
Latently infected B cells can then go on to produce proteins that function to promote cellular growth through modification of normal signaling pathways. EBV promotes the development of malignant B cells via proteins that limit apoptosis in cells that had the c-myc translocation. Apoptosis is limited by EBV through various means such as the EBNA-1 protein, BHF1 protein, EBER transcripts, vIL-10 gene, BZLF1, and LMP1. Recent studies have also shown that the EBV noncoding RNA EBER2 can increase Burkitt lymphoma cell growth by upregulating UCHL1, a cellular deubiquitinase. Malaria has been found to cause genomic instability in endemic Burkitt lymphoma. Malaria can lead to the reactivation of latent EBV and also MYC translocations via activation of the toll-like receptor 9. Malaria also promotes B-cell proliferation by altering the regular immune response. The immune system targets antigens and eliminates most B cells infected with EBV. Downregulation of antigens targeted by the immune system leads to the development of persistent B cells. These B cells can then undergo further mutations that promote cancer development.