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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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Characterization of IL-6 tg and AID−/− IL-6 tg mice. (A) Flow cytometry analysis of cells from hyperplastic lymph nodes from IL-6 tg and AID−/−IL-6 tg mice. Numbers indicate percentages of cells in a given quadrant. (B) AID accelerates the development of disease in IL-6 tg mice. IL-6 tg mice and AID−/−IL-6 tg mice were killed when they developed enlarged lymph nodes. The average time of death for IL-6 tg was 5.5 mo (n = 8) and 9.2 mo for AID−/−IL-6 tg mice (n = 8; P = 0.0001476 using a two-tailed Student's t test assuming unequal variance). Each point represents one mouse, and the black bars indicate the average time of death.
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fig1: Characterization of IL-6 tg and AID−/− IL-6 tg mice. (A) Flow cytometry analysis of cells from hyperplastic lymph nodes from IL-6 tg and AID−/−IL-6 tg mice. Numbers indicate percentages of cells in a given quadrant. (B) AID accelerates the development of disease in IL-6 tg mice. IL-6 tg mice and AID−/−IL-6 tg mice were killed when they developed enlarged lymph nodes. The average time of death for IL-6 tg was 5.5 mo (n = 8) and 9.2 mo for AID−/−IL-6 tg mice (n = 8; P = 0.0001476 using a two-tailed Student's t test assuming unequal variance). Each point represents one mouse, and the black bars indicate the average time of death.

Mentions: IL-6 tg mice develop hyperplastic lymph nodes that contain large numbers of class-switched plasmacytes, a portion of which express GL7 and CD138 (24, 45, 46). Plasmacytosis is believed to develop in these mice because IL-6 attenuates apoptosis and promotes proliferation and differentiation of late-stage B cells, allowing for the accumulation of translocations between IgH and c-myc (45). Although a majority of the c-myc translocation breakpoints are at the Ig switch region, a small fraction occur at the V-JH region (46) and therefore resemble the translocations found in endemic Burkitt's lymphoma (for review see references 7 and 8). To determine whether AID is required for translocations between the Ig V-JH region and c-myc, we generated AID-deficient IL-6 tg mice (AID−/−IL-6 tg) by breeding (24). AID−/−IL-6 tg mice developed lymph node hyperplasia and plasmacytosis with a slightly delayed onset compared with IL-6 tg mice, and there was no detectable class switching in the AID−/−IL-6 tg mice (Fig. 1, A and B) (24).


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)

Characterization of IL-6 tg and AID−/− IL-6 tg mice. (A) Flow cytometry analysis of cells from hyperplastic lymph nodes from IL-6 tg and AID−/−IL-6 tg mice. Numbers indicate percentages of cells in a given quadrant. (B) AID accelerates the development of disease in IL-6 tg mice. IL-6 tg mice and AID−/−IL-6 tg mice were killed when they developed enlarged lymph nodes. The average time of death for IL-6 tg was 5.5 mo (n = 8) and 9.2 mo for AID−/−IL-6 tg mice (n = 8; P = 0.0001476 using a two-tailed Student's t test assuming unequal variance). Each point represents one mouse, and the black bars indicate the average time of death.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2118712&req=5

fig1: Characterization of IL-6 tg and AID−/− IL-6 tg mice. (A) Flow cytometry analysis of cells from hyperplastic lymph nodes from IL-6 tg and AID−/−IL-6 tg mice. Numbers indicate percentages of cells in a given quadrant. (B) AID accelerates the development of disease in IL-6 tg mice. IL-6 tg mice and AID−/−IL-6 tg mice were killed when they developed enlarged lymph nodes. The average time of death for IL-6 tg was 5.5 mo (n = 8) and 9.2 mo for AID−/−IL-6 tg mice (n = 8; P = 0.0001476 using a two-tailed Student's t test assuming unequal variance). Each point represents one mouse, and the black bars indicate the average time of death.
Mentions: IL-6 tg mice develop hyperplastic lymph nodes that contain large numbers of class-switched plasmacytes, a portion of which express GL7 and CD138 (24, 45, 46). Plasmacytosis is believed to develop in these mice because IL-6 attenuates apoptosis and promotes proliferation and differentiation of late-stage B cells, allowing for the accumulation of translocations between IgH and c-myc (45). Although a majority of the c-myc translocation breakpoints are at the Ig switch region, a small fraction occur at the V-JH region (46) and therefore resemble the translocations found in endemic Burkitt's lymphoma (for review see references 7 and 8). To determine whether AID is required for translocations between the Ig V-JH region and c-myc, we generated AID-deficient IL-6 tg mice (AID−/−IL-6 tg) by breeding (24). AID−/−IL-6 tg mice developed lymph node hyperplasia and plasmacytosis with a slightly delayed onset compared with IL-6 tg mice, and there was no detectable class switching in the AID−/−IL-6 tg mice (Fig. 1, A and B) (24).

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