Types of genetic abnormality

The types of genetic abnormality found in lymphoma may be crudely divided into two main classes: those that foster increased proliferation, and those that inhibit programmed cell death, or apoptosis. The classical gene in lymphomagenesis that induces proliferation is c-MYC. Burkitt's lymphoma, one of the most rapidly dividing lymphomas, is the archetype of a lymphoma that overexpresses c-MYC by the t(8;14). c-MYC is a helix-loop-helix leucine zipper transcription factor which requires heterodimerization with the protein MAX to activate transcription and induce proliferation. Targets of this dimer include genes controlling cell cycle progression, cell growth, metabolism, differentiation, and apoptosis. The net effect of c-MYC expression is generally an increase in proliferation; however, this effect is context-specific. In some cells, c-MYC overexpression can induce cell cycle arrest or apoptosis via p53. Therefore, it may require an apoptotic defect to permit c-MYC overexpression.

BCL-2 is an oncogene that does not directly foster increased proliferation, but rather opposes apoptosis. It does this at least in part by binding and sequestering pro-apoptotic BCL-2 family members, preventing them from communicating or executing death signals, especially at the mitochondrion. It is classically overexpressed in the indolent follicular lymphoma due to the t(14;18). Other apoptotic defects often found in lymphoma include those allowing the activation or stabilization of NF-kB transcription factors.

A frequent hallmark of translocations found in B-cell lymphomas is their exploitation of immunoglobulin (Ig) gene regulatory elements to drive expression of an oncogene in a malignant B cell or B-cell precursor. Burkitt's lymphoma is an example of a lymphoma characterized by the overexpression of c-MYC. While the most common translocation is t(8;14), which puts c-MYC under the control of the Ig heavy chain (IgH) transcription elements, the less common t(2;8) and t(8;22) are also found, putting c-MYC transcription under the control of the light-chain K and X transcription elements, respectively. The t(14;18) found in follicular lymphoma drives BCL-2 expression using IgH transcription elements. The BCL-6 expression found in many DLBL cases is often driven by IgH, IgK, and IgX elements in the t(3;14), t(2;3) and t(3;22) respectively. PAX 5 expression in lymphoplasmacytoid lymphoma and cyclin D1 expression in mantle cell lymphoma are likewise driven by the t(9;14) and t(11;14) which exploit the IgH locus.

Improved techniques of genetic study have allowed the identification of a large number of chromosomal translocations, the most common of which are shown in Table 10.2. Those abnormalities which are the most common, or which have been demonstrated to have the greatest impact on prognosis or treatment, are described. Figure 10.3 shows the molecular pathogenesis, putative cell of origin within B-cell development within the lymph node and germinal center, and the immunophenotype of the most common types of lymphomas. The molecular pathogenesis of chronic lym phocytic leukemia/small lymphocytic lymphoma remains unknown.

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