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Burkitt's lymphoma (BL)

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Overview

Types of Burkitt's lymphoma

Burkitt's lymphoma is highly aggressive proliferative B-cell tumor that includes three types:

Phenotype

BL is often multifocal and almost always arises in extra-nodal sites. In addition to the jaw, other common sites include ovary, mammary gland, liver, intestine and kidneys. BL is rapidly fatal if untreated, although chemotherapy can provide good long-term survival.

Histologically BL consists of rapidly proliferating, small, non-cleaved B-cells infiltrated with large, pale staining histiocytes which give the classic "starry sky" pattern.

Genetic abnormalities

All BL tumors, whether EBV associated or not, show one or more chromosomal translocations (8:14, 8:2 or 8:22) which brings c-myc oncogene on chromosome 8 under the influence of Ig (immunoglobulin) heavy (chr. 14) or light (kappa on chr. 2, lambda on chr. 22) chain promoters and causes its constitutive expression.

c-myc is a cellular oncogene which drives the cell to continuous proliferation and inhibits differentiation. Thus, this translocation is regarded as pivotal in BL development.

Gene expression

Most EBV-positive cases exhibit highly restrictive pattern of expression of latent encoded proteins, only expressing EBNA-1 and EBERs (latency I). However, it was recently reported that some cases, in addition to EBNA-1 and EBERs, express EBNA-3A, EBNA-3B, EBNA-3C, and EBNA-LP (EBNA leader protein) but still lack EBNA-2 and Latent Membrane Proteins (LMPs).

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Role of Epstein-Barr virus in sustaining BL

Viral plasmids are distributed unevenly but only EBV+ host cells survive

Epstein-Barr virus exists in latently infected tumor cells in form of extra-chromosomal circular DNA (episome or plasmid). For cultured cells transfected with foreign DNA, maintenance of the DNA is a burden unless it does not encode genes that are necessary for the cells' survival and proliferation in adverse environments (for example, antibiotic resistance).

It was found that not all EBV plasmids are duplicated each cell cycle which leads to a loss of EBV plasmids from some of the daughter cells. EBV-associated human tumor cells remain EBV-positive throughout the cancer development, thus demonstrating that EBV sustains the tumor cells in vivo. To provide selective advantages to infected cells the virus can promote their proliferation or/and inhibit apoptosis. Most current evidence indicates that EBV minimally blocks apoptosis in Burkitt's lymphoma's cells.

Unorthodox host-parasite relationship: host cells are using virus to their advantage

Traditionally, viruses are considered to be obligate cellular parasites: they infect the host's cell, hijack the cell's resources, produce progeny leading to cell's death by lysis, by apoptosis, or by immune response. But in case of carcinogenic viruses, the roles appear to be reversed: by retaining viral genes the tumor cell acquires properties that give it selective advantage over uninfected cells wherereas the virus is usually incapable to reproduce.

EBV in Burkitt's lymphoma is not lymphoproliferaive

EBV is known for its ability to drive resting, primary B cells to proliferate (a process referred as transformation). The Latent Membrane Protein 1 (LMP1), a classical oncogene that alters cellular cycle's signaling pathways, was found to be responsible for B-cell transformation and subsequent proliferation and typically its withdrawal causes transformed cells derived from Post-Transplant Lymphoproliferative Disorder (PTLD) or Hodgkin's lymphomas to cease proliferation.

Burkitt's lymphomas are aggressive tumors but they do not express LMP1. In addition, none of the pathways central to LMP1-mediated proliferation (for example, JAK/STAT or AP-1 pathways) are activated in Burkitt's lymphoma. It is suggested that LMP1 is not expressed in BL both because it is immunogenic, and because it does not provide an optimal proliferative stimulus for the evolving tumor, which is provided by the translocated c-myc oncogene, a hallmark of all Burkitt's lymphomas. The chromosomal translocations that are characteristic of all BLs, is the primary oncogenic event in the pathogenesis of BL irrespective of the association with EBV, however, EBV infection (specifically, EBNA1 expression) together with other contributing factors (such as HIV and malaria) might increase the likelihood of genetic accidents giving rise to the translocations as well as providing further complementary support to mutated cells.

EBV blocks apoptosis in B cells

Normal B-lymphocytes are controlled by multiple regulators of apoptosis. Reflecting their cells of origin, Burkitt's lymphomas are also prone to apoptosis. Moreover, misregulated c-myc sensitizes cells to apoptosis as well. A defining histopathological pattern of Burkitt's lymphoma is "starry sky" appearance, resulting from the infiltration of the tumor by phagocytic macrophages cleaning out apoptotic tumor cells. Despite this, Burkitt's lymphomas grow extremely rapidly.

Most viral genes expressed latently in B cells have been reported under some conditions to block several pro-apoptotic signaling pathways (for example, Bim, p53, PUMA). EBNA1 expressed in all EBV-positive Burkitt's lymphomas is considered principal anti-apoptotic agent. The viral RNAs (EBERs and miRNAs) have also been demonstrated to possess anti-apoptotic activity and are ubiquitously expressed in Burkitt's lymphomas.

EBV shields BL from host's immune response

The immune system is capable of generating both CD4+ and CD8+ T-cell responses to several latent and lytic phase EBV-associated antigens (Ags), such as LMP1, LMP2, EBNA2, and EBNA3. Unfortunately, BL cells generally express only the EBNA1 protein (Latency 1 program, EBV latency and persistence), which is poorly antigenic and has little to no HLA class response. Many aspects of BL's capabilities to evade the host's immune response are described in review by God JM & Haque A., 2010 (see references below).

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References