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A role for AID in chromosome translocations between c-myc and the IgH variable region.

Dorsett Y, Robbiani DF, Jankovic M, Reina-San-Martin B, Eisenreich TR, Nussenzweig MC - J. Exp. Med. (2007)

Bottom Line: However, in mature B cells undergoing activation-induced cytidine deaminase (AID)-dependent somatic hypermutation (SHM), duplications or deletions that would necessitate a double-strand break make up 6% of all the Ig V-J(H) region-associated somatic mutations.Furthermore, DNA breaks can be detected at this locus in B cells undergoing SHM.Here, we report that AID is required for c-myc to Ig V-J(H) translocations induced by IL-6.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10021, USA.

ABSTRACT
Chromosome translocations between oncogenes and the region spanning the immunoglobulin (Ig) heavy chain (IgH) variable (V), diversity (D), and joining (J) gene segments (Ig V-J(H) region) are found in several mature B cell lymphomas in humans and mice. The breakpoints are frequently adjacent to the recombination signal sequences targeted by recombination activating genes 1 and 2 during antigen receptor assembly in pre-B cells, suggesting that these translocations might be the result of aberrant V(D)J recombination. However, in mature B cells undergoing activation-induced cytidine deaminase (AID)-dependent somatic hypermutation (SHM), duplications or deletions that would necessitate a double-strand break make up 6% of all the Ig V-J(H) region-associated somatic mutations. Furthermore, DNA breaks can be detected at this locus in B cells undergoing SHM. To determine whether SHM might induce c-myc to Ig V-J(H) translocations, we searched for such events in both interleukin (IL) 6 transgenic (IL-6 tg) and AID(-/-) IL-6 tg mice. Here, we report that AID is required for c-myc to Ig V-J(H) translocations induced by IL-6.

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Somatic mutations in translocated IgH. Analysis of 32,654 bp of IgH sequence from c-myc/IgH translocations identified 20 different mutations (mutation frequency = 0.61 × 10−3), excluding the two mutations found within 4 nts of breakpoints. Excluding the three mutations within 3 nts of the breakpoint, analysis of 16,960 bp of c-myc identified three different mutations (mutation frequency = 0.18 × 10−3). The overall mutation rate within 20 nts of a breakpoint on either side of the translocation was 5.4 × 10−3. Asterisks indicate mutations within 20 nts of a breakpoint.
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fig4: Somatic mutations in translocated IgH. Analysis of 32,654 bp of IgH sequence from c-myc/IgH translocations identified 20 different mutations (mutation frequency = 0.61 × 10−3), excluding the two mutations found within 4 nts of breakpoints. Excluding the three mutations within 3 nts of the breakpoint, analysis of 16,960 bp of c-myc identified three different mutations (mutation frequency = 0.18 × 10−3). The overall mutation rate within 20 nts of a breakpoint on either side of the translocation was 5.4 × 10−3. Asterisks indicate mutations within 20 nts of a breakpoint.

Mentions: Although there was no correlation between the position of the breakpoints and the RGYW motifs, which are the preferred targets of AID, the translocated Ig V-JH region was somatically mutated at a frequency of ∼0.6 × 10−3 mutations per basepair (Fig. 4). This rate of mutation is similar to that reported for the Ig V-JH region in B cells undergoing hypermutation (47). Derivative 12 and 15 IgH sequences had a similar frequency of hypermutation, suggesting that SHM must have occurred before or during translocation. Interestingly, the overall position of the mutations mirrored the positions of the translocation breakpoints (compare Figs. 3 and Figs.4), supporting the idea that regions prone to SHM are susceptible to translocations. Excluding nucleotide insertions at the breakpoint, the rate of mutation within 20 bp of either side of the translocation breakpoints was almost 10-fold higher (5.4 × 10−3) than that seen overall for IgH in our translocations. This implies that c-myc/IgH translocations are resolved through error-prone repair, or that translocation breakpoints occur at or immediately adjacent to hypermutated sequences. Discounting mutations within 20 bp of the breakpoint, we identified three mutations in c-myc, resulting in a mutation rate that is above background (∼0.2 × 10−3) but approximately threefold lower than the rate observed for IgH (Fig. 4). These results suggest that c-myc translocations to the Ig V-JH region in IL-6 tg mice occur during or after Ig V-JH region SHM (28, 47, 48).


A role for AID in chromosome translocations between c-myc and the IgH variable region.

Dorsett Y, Robbiani DF, Jankovic M, Reina-San-Martin B, Eisenreich TR, Nussenzweig MC - J. Exp. Med. (2007)

Somatic mutations in translocated IgH. Analysis of 32,654 bp of IgH sequence from c-myc/IgH translocations identified 20 different mutations (mutation frequency = 0.61 × 10−3), excluding the two mutations found within 4 nts of breakpoints. Excluding the three mutations within 3 nts of the breakpoint, analysis of 16,960 bp of c-myc identified three different mutations (mutation frequency = 0.18 × 10−3). The overall mutation rate within 20 nts of a breakpoint on either side of the translocation was 5.4 × 10−3. Asterisks indicate mutations within 20 nts of a breakpoint.
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Related In: Results  -  Collection

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fig4: Somatic mutations in translocated IgH. Analysis of 32,654 bp of IgH sequence from c-myc/IgH translocations identified 20 different mutations (mutation frequency = 0.61 × 10−3), excluding the two mutations found within 4 nts of breakpoints. Excluding the three mutations within 3 nts of the breakpoint, analysis of 16,960 bp of c-myc identified three different mutations (mutation frequency = 0.18 × 10−3). The overall mutation rate within 20 nts of a breakpoint on either side of the translocation was 5.4 × 10−3. Asterisks indicate mutations within 20 nts of a breakpoint.
Mentions: Although there was no correlation between the position of the breakpoints and the RGYW motifs, which are the preferred targets of AID, the translocated Ig V-JH region was somatically mutated at a frequency of ∼0.6 × 10−3 mutations per basepair (Fig. 4). This rate of mutation is similar to that reported for the Ig V-JH region in B cells undergoing hypermutation (47). Derivative 12 and 15 IgH sequences had a similar frequency of hypermutation, suggesting that SHM must have occurred before or during translocation. Interestingly, the overall position of the mutations mirrored the positions of the translocation breakpoints (compare Figs. 3 and Figs.4), supporting the idea that regions prone to SHM are susceptible to translocations. Excluding nucleotide insertions at the breakpoint, the rate of mutation within 20 bp of either side of the translocation breakpoints was almost 10-fold higher (5.4 × 10−3) than that seen overall for IgH in our translocations. This implies that c-myc/IgH translocations are resolved through error-prone repair, or that translocation breakpoints occur at or immediately adjacent to hypermutated sequences. Discounting mutations within 20 bp of the breakpoint, we identified three mutations in c-myc, resulting in a mutation rate that is above background (∼0.2 × 10−3) but approximately threefold lower than the rate observed for IgH (Fig. 4). These results suggest that c-myc translocations to the Ig V-JH region in IL-6 tg mice occur during or after Ig V-JH region SHM (28, 47, 48).

Bottom Line: However, in mature B cells undergoing activation-induced cytidine deaminase (AID)-dependent somatic hypermutation (SHM), duplications or deletions that would necessitate a double-strand break make up 6% of all the Ig V-J(H) region-associated somatic mutations.Furthermore, DNA breaks can be detected at this locus in B cells undergoing SHM.Here, we report that AID is required for c-myc to Ig V-J(H) translocations induced by IL-6.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10021, USA.

ABSTRACT
Chromosome translocations between oncogenes and the region spanning the immunoglobulin (Ig) heavy chain (IgH) variable (V), diversity (D), and joining (J) gene segments (Ig V-J(H) region) are found in several mature B cell lymphomas in humans and mice. The breakpoints are frequently adjacent to the recombination signal sequences targeted by recombination activating genes 1 and 2 during antigen receptor assembly in pre-B cells, suggesting that these translocations might be the result of aberrant V(D)J recombination. However, in mature B cells undergoing activation-induced cytidine deaminase (AID)-dependent somatic hypermutation (SHM), duplications or deletions that would necessitate a double-strand break make up 6% of all the Ig V-J(H) region-associated somatic mutations. Furthermore, DNA breaks can be detected at this locus in B cells undergoing SHM. To determine whether SHM might induce c-myc to Ig V-J(H) translocations, we searched for such events in both interleukin (IL) 6 transgenic (IL-6 tg) and AID(-/-) IL-6 tg mice. Here, we report that AID is required for c-myc to Ig V-J(H) translocations induced by IL-6.

Show MeSH
Related in: MedlinePlus