USMLE – Lymphoma
A number of chromosomal abnormalities have been observed in human lymphomas. The earliest one found and the one first characterized in detail involves a translocation between chromosomes 8 and 14 t(8;14) in Burkitt’s lymphoma, an aggressive B-cell lymphoma seen primarily in children in parts of Central Africa. Later, two other translocations involving chromosome 8 were observed: t(2;8) and t(8;22). About 80% of patients with Burkitt’s lymphoma have a t(8:14)(q24; q32) translocation: 15% have a t(8;22)(q24; q11 ) translocation: and 5% have a t(2;8)(p11;q24) translocation. All of these chromosomes carry genes of the immunoglobulin family: 14q32, 22q11, and 2p11 contain the human immunoglobulin heavy chain, respectively, suggesting that immunoglobulin genes are involved in a key way in Burkitt’s lymphoma. Similar translocations have now been found in other B-cell malignancies, including a t(14;18)(q32; q21) in about 85% of follicular lymphomas, a low grade B-cell lymphoma common in North America and western Europe, and a t(11;14)(q13; q32) in CLL, diffuse B-cell lymphoma, and multiple myeloma.
T-cell malignancies are less common than B-cell malignancies and often have chromosomal alterations involving the 14q11 locus, which contains the T-cell-receptor alpha and sigma genes. One or both of these genes are involved in several translocations including t(8;14)(q24; q11), t(10:14)(q24; q11), and t(11;14)(p13;q11).
Thus, in both T- and B-cell malignancies, translocations involving the immunoglobulin superfamily of genes are frequently observed. The t(8;14) translocation first observed in Burkitt’s lymphoma involves translocation of the c-myc protooncogene from chromosome 8 to 14 in the locus of the immunoglobin heavy chain gene (IgH).
Chromosome 14q32 translocations are seen in several lymphoid malignancies.” For example, about 90% of follicular lymphomas have a t(14;18)(q32: q21) translocation that involves the Jh region of the IgH locus and a gene on chromosome 18 called bel-2. This leads to deregulation of the bel-2 gene, a gene involved in maintenance of cell proliferation and inhibition of programmed cell death (apoptosis),
A t(11:14) translocation is found in multiple myeloma and in 10% to 30% of CLL patients. This involves the Jh locus on 14 and a breakpoint cluster on chromosome 11 called bcl-1.
In some cases, two or more translocation events may occur, and when they do, a more aggressive disease may result. For example, a t(l4;18) translocation involving the bcl-2 gene cluster may result in a low-grade B-cell malignancy; but in the course of the disease, a second translocation event involving the c-myc gene on chromosome 8 may occur, leading to progression to more aggressive, high-grade lymphoma or acute leukemia.
Cytogenetic studies have also shown that chromosome 7 band q34-35, which contains the T-cell receptor beta gene, is a common site for translocation in T-cell neoplasms. One interesting translocation of this type is t(7;9)(q34; q34), found in cases of ALL. This involves the TCR-beta gene on chromosome 7 and a newly described gene called TAN-1 on 9. The sequence of this gene indicates that it encodes a protein that is highly homologous to the Notch gene product of the fruit fly Drosophila. Notch is an integral membrane protein involved in determination of embryonic cell fates in Drosophila. In mice and humans. TAN-l is highly expressed and appears to be involved in normal lymphoid differentiation. The TAN-l mRNA found in ALL cells, however, is truncated and appears to contribute to transformation or progression in some T-cell malignancies.