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The Immunoglobulin Heavy Chain Gene 2122 1 8 M a R C H 2 0 1 0 I V O L U M E 1 1 5 , N U M B E R 1 1 Blood
| Content Provider | Semantic Scholar |
|---|---|
| Author | Vinatzer Welzel Marculescu R. Sica, Antonio Humanitas, Clinico |
| Abstract | (IgH) is composed of a number of variable (V), diversity (D), joining (J), and constant region genes. In normal B cells these genes recom-bine via formation of double-stranded DNA breaks to generate functional Ig genes and protein with high antigen affinity. This process, known as V(D)J recombination, is the main mechanism for generating antigen-receptor diversity. The breaks and recombination events that occur during this process explain the tendency for chromosomal translocations in B-cell lymphomas to involve the Ig loci. However, the precise molecular mechanisms underlying these translocations remain unknown and different mechanisms have been proposed in various lymphoma types. In this issue of Blood, Murga Penas and colleagues show that the t(14;18)(q32;q21) is the result, at least in part, of illegitimate V(D)J recombination. 4 By analyzing the sequence of the breakpoints at the IgH locus on chromosome 14, they identified findings typical of V(D)J-mediated recombination, that is, presence of a recombination signal sequence and evidence of coding end processing, including nucleotide deletions and insertion of non– template-dependent (N) nucleotides. The authors also found insertions of templated (T)– nucleotides at the junction sites. T-nucleotides are short copies of at least 5 nucleotides copied from the regions surrounding the breakpoints and often contain point mutations and/or insertions or deletions. Because T-nucleotides have not been described in normal V(D)J recombination products, their presence suggests that they are generated by error-prone template-dependent DNA synthesis rather than illegitimate V(D)J recombination. In contrast , analysis of the chromosome 18 breakpoints showed findings inconsistent with V(D)J recom-bination mechanisms. The authors identified an 87 base pair (bp) region in which the breakpoints of all cases clustered in the 5Ј noncoding region of MALT1. In at least one case, analysis of the DH-MALT1 junction showed a duplication of 8 MALT1 nucleotides, suggesting a staggered double-stranded DNA break. Similar findings have been found in other chromosomal translo-cations, such as t(14;18)/IgH-BCL2 in follicular lymphoma and t(11;14)/CCND1-IgH in mantle cell lymphoma, suggesting that these chromo-somal translocations are generated by similar mechanisms. 5,6 In these translocations, illegitimate V(D)J mechanisms mediate recombination at the IgH locus, T-nucleotides are reported at the breakpoints, and breakpoint clusters occur in the BCL2 and CCND1 loci. Another interesting implication of this study is the timing of translocations: when in B-cell differentiation do they occur? It seems intuitive that a particular chromosomal translocation may arise at a specific stage of B-cell differentiation, and therefore contributes to the biologic and … |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://www.bloodjournal.org/content/bloodjournal/115/11/2122.full.pdf?sso-checked=true |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
