Chromosomal translocations involved in non-Hodgkin lymphomas

Archives of Pathology & Laboratory Medicine, Sep 2003 by Vega, Francisco, Medeiros, L Jeffrey

* Context.-The discovery that recurrent chromosomal translocations are involved in the pathogenesis of non-Hodgkin lymphomas has greatly improved our understanding of these diseases and revolutionized their diagnosis.

Objective.-To review the mechanisms by which chromosomal translocations occur and contribute to the pathogenesis of various types of non-Hodgkin lymphomas and to review the utility of molecular genetic methods for the assessment of these translocations.

Data Sources and Study Selection.-Primary research studies and reviews published in the English language that focus on chromosomal translocation and non-Hodgkin lymphomas.

Data Extraction and Synthesis.-Chromosomal translocations, which usually result in oncogene activation, occur in many types of B- and T-cell lymphoma, and their detection is helpful for establishing an accurate diagnosis and monitoring disease following therapy. However, the precise mechanisms that explain how translocations occur remain unknown, although for some types of translocations a clear relationship has been established with immunoglobulin gene rearrangement mechanisms. In recent years, a number of genes deregulated by chromosomal translocations have been identified, and the detailed molecular mechanisms by which chromosomal translocations contribute to the pathogenesis of non-Hodgkin lymphoma are beginning to be elucidated.

Conclusions.-Molecular genetic analysis has played a major role in improving our understanding of B- and T-cell non-Hodgkin lymphomas and has allowed more precise definition of lymphoma types. Molecular genetic tests to detect these translocations are important ancillary tools for the diagnosis and classification of malignant lymphomas.

Chromosomal translocations in non-Hodgkin lymphomas can be subdivided into 2 general types. In the first type, an intact oncogene (or intact coding region) is juxtaposed via the translocation with another gene, usually an antigen receptor gene. As a result, the oncogene becomes transcriptionally deregulated. Historically, this was the first type of translocation discovered in non-Hodgkin lymphomas. Examples of this type include the t(8;14) in Burkitt lymphoma/leukemia and the t(14;18) in follicular lymphoma. In the second type of translocation, 2 genes (usually non-antigen receptor genes) are disrupted, and portions of each gene are juxtaposed, resulting in a fusion gene, chimeric mRNA, and a novel protein. This type of chromosomal translocation occurs in some types of non-Hodgkin lymphoma, such as the t(2;5) in anaplastic large cell lymphoma (ALCL), but is best known in acute and chronic myeloid leukemias.

MECHANISMS OF CHROMOSOMAL TRANSLOCATIONS

Overall, the precise molecular mechanisms underlying chromosomal translocation remain largely unknown, and different mechanisms have been proposed to explain recurrent translocations in various lymphoma types. In some cases, the evidence suggests that translocation is a result of aberrant V(D)J recombinase activity, because cryptic heptamer/nonamer consensus sequences are present in the immediate vicinity of the translocation break-points.1,2

The antigen receptor loci of B cells may be subjected to 4 types of modification: recombination of the variable (V), diversity (D), and joining (J) regions, somatic hypermutation of the V segments, immunoglobulin heavy-chain (IgH) gene class switching, and receptor editing. Occasional failures in the control of these processes appear to play an important role in the generation of chromosomal translocations in B-cell lymphomas. These events occur mainly at 2 stages of B-cell development: during V region recombination in B-cell precursors in the bone marrow and during B-cell differentiation in the germinal center microenvironment. Chromosome translocations in T-cell lymphomas also may arise from analogous errors of T-cell receptor (TCR) gene V(D)J recombination.2 However, somatic hypermutation of V segments is rare, and class switching of the TCR genes does not occur in T cells.

V(D)J Recombination

The development of B cells in the bone marrow is initiated by a site-specific recombination reaction, V(D)J recombination, of the IgH and Ig light-chain genes ([kappa] and [lambda]).3 For formation of the V region exon of the IgH chain, V, D, and J gene segments are joined, whereas the V region exons of [kappa] and [lambda] light chains are composed only of V and J segments.3,4 As shown for IgH in Figure 1, first a D^sub H^ segment is joined with a J^sub H^ segment. This joining is followed by a V^sub H^ to D^sub H^J^sub H^ joining, which can be either in frame (correct for encoding antibody sequences) or out of frame. When in-frame VDJ joining is achieved, and the precursor cell is now a B cell that can proceed with maturation by undergoing Ig light-chain gene rearrangements. Following out-of-frame VDJ joining, a second attempt at VDJ joining occurs on the other allele.

Recombination involves the introduction of double-strand breaks in DNA by the products of the recombination-activating genes, RAG-1 and RAG-2.5 These breaks occur at specific recognition signal sequences (RSSs) adjacent to the V, D, and J elements (3' to the V regions, 5' and 3' to the D regions, and 5' to the J regions). An RSS is composed of conserved heptamer and nonamer motifs separated by a relatively nonconserved spacer region of either 12 or 13 base pairs (bp), and efficient recombination requires one RSS of each type. Several other proteins are needed in this process, including DNA ligase IV; DNA-dependent protein kinase; Ku, which is a heterodimer (Ku 70:Ku 80) that associates tightly with DNA-dependent protein kinase; and the DNA-repair protein, x-ray repair complementing defective in Chinese hamster 4 (XRCC4).6 The characteristic steps in the V(D)J recombination process are illustrated in Figure 2.