Genetic rearrangements: the role of chromosomal translocations
A fundamental mechanism in the development of many lymphomas is the movement (translocation) of chromosome segments containing proto-oncogenes into active transcription zones. For lymphocytes, these zones are the immunoglobulin gene loci (in B cells) or T-cell receptor gene loci (in T cells).
Key translocations in B-cell lymphomas:
- Burkitt lymphoma: the c-myc proto-oncogene from chromosome 8 is translocated to chromosome 14, directly adjacent to the immunoglobulin heavy chain gene (IGH). Less commonly, c-myc may translocate to chromosome 2 (to the IGK locus encoding the $\kappa$ chain) or to chromosome 22 (to the IGL locus, $\lambda$ chain). If the bcl-2 gene translocation is added to this mutation, the malignancy of the tumor increases sharply.
- Follicular B-cell lymphoma: the bcl-2 proto-oncogene from chromosome 18 is translocated to the IGH gene on chromosome 14.
Thus, tumor growth is directly linked to the natural mechanisms of lymphocyte activation, during which recombination of antigen-recognition receptor genes takes place.
Viral triggers and cofactors
Viruses often exploit the natural instability of the lymphocyte genome; however, a virus alone is not sufficient for tumor development—synergism with additional environmental factors (cofactors), which often have endemic distribution, is required.
- Epstein-Barr virus (EBV): is capable of causing both benign processes (infectious mononucleosis) and malignant ones (Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma). In mononucleosis, the virus stimulates mitogenesis genes without chromosomal rearrangements. Burkitt lymphoma develops only if the c-myc proto-oncogene translocation occurs against the background of EBV infection.
- HTLV-1 virus: a lymphotropic retrovirus with an affinity for CD4+ T cells. Unlike HIV, it does not destroy but transforms infected lymphocytes, leading to adult T-cell leukemia/lymphoma (frequently found in the southern islands of Japan, where the necessary cofactors are prevalent).
T-cell lymphomas and ataxia-telangiectasia
In a healthy body, B cells undergo malignant transformation much more frequently than T lymphocytes. However, the situation reverses in profound immunosuppression (due to chemotherapy, radiation, or primary immunodeficiencies).
A prime example is ataxia-telangiectasia. In this inherited disease, chromosomal instability is combined with immunodeficiency, often leading to T-cell leukemia. The pathogenesis is not virus-related: the TCL1 gene (an analog of bcl-2 on chromosome 14) translocates to T-cell receptor gene regions. The target is most often the TCRA locus (14q11) encoding the $\alpha/\delta$ receptor chains, and less commonly the TCRB locus (7q35).
Tumor cell functionality and the immunodeficiency paradox
Transformed mature lymphocytes retain their basic functions, receptors, and migration capacity, but completely lose sensitivity to the body's regulatory signals.
This phenomenon is well studied in multiple myeloma (a plasma cell neoplasm). Malignant cells continue to actively secrete antibodies of a single random specificity. A homogeneous peak appears in blood serum—the M-protein (proof of the monoclonal origin of the tumor).
Despite the excess of antibodies, the patient develops severe immunodeficiency. There are two reasons:
- Tumor antibodies are monoclonal and cannot provide protection against a variety of real-world infections.
- The body attempts to stop the uncontrolled synthesis of antibodies and triggers suppressive regulatory mechanisms. The tumor ignores these signals, whereas normal (healthy) lymphocytes are effectively suppressed.
To remember translocations: "Burkitt is 8/14 (c-myc), and Follicular is 18/14 (bcl-2)." Chromosome 14 (IGH gene) is a common target for both B-cell lymphomas.
Class and exam questions
What is the difference between infectious mononucleosis and Burkitt lymphoma if both are associated with EBV?
Mononucleosis is a reversible proliferation in which the virus activates mitogenesis, but chromosomal rearrangements are absent. Burkitt lymphoma develops only when an irreversible translocation of the c-myc gene to the immunoglobulin locus is added to the viral infection.
How to confirm tumor monoclonality if it does not secrete antibodies (M-protein)?
Genetic analysis of BCR or TCR receptor gene rearrangements is performed. In all cells of a single tumor clone, the pattern of the rearrangement will be absolutely identical, yet unique to that specific patient.
Are tumor cytotoxic T cells (CD8+) capable of destroying target cells?
Technically they retain this functional potential, but in practice, verifying this in vivo is almost impossible because the specificity of their T-cell receptors (TCR) is unknown and random.
What else to study on this topic
- Cytokine profile of various types of T-cell lymphomas
- Mechanisms of normal immune response suppression in multiple myeloma
- Migration features of malignant T and B lymphocytes
- Interaction of EBV with endemic cofactors in Africa
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