Immunoglobulin V gene replacement is caused by the intramolecular DNA deletion mechanism.

Usuda, S; Takemori, Toshitada; Matsuoka, Masao; Shirasawa, Takuji; Yoshida, Kazuya; Mori, A.; Ishizaka, Kimishige; Sakano, Hitoshi

doi:10.1002/j.1460-2075.1992.tb05093.x

Cited by 31 publications

(25 citation statements)

References 40 publications

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“…Although Usuda et al [37] observed another form of such rearrangement in vivo which involved cryptic RSS in the switch regions of the constant region genes, this recombination seems to be related to class switching rather than V region gene rearrangement. Moreover, two cases of VH to VHDHJH rearrangement in human, which apparently occurred in vivo, were fortuitously rescued as a B lymphoma cell line or as a PCR product from leukemic patients [41, 421. In contrast, heterozygous T15i mutant mice provide us with a system where V region gene rearrangement involving cryptic RSS takes place constantly in vivo.…”

Section: Uniqueness Of T15i Mutant Mice In the Study Of The V Region mentioning

confidence: 91%

Rearrangement of upstream D_H and V_H genes to a rearranged immunoglobulin variable region gene inserted into the DQ52‐J_H region of the immunoglobulin heavy chain locus

1995

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We investigated gene rearrangements in the mutant IgH locus of a mouse strain generated by insertion of a rearranged heavy chain variable region gene (VT15) into the DQ52-JH region through gene targeting. In more than half of the B cells of heterozygous mutant mice, the mutant IgH locus was silenced by the rearrangement of an endogenous DH or DH and VH gene to the inserted VT15 gene. In these cases, a functional VHDHJH gene was present on the wild-type allele. The silencing rearrangement appeared to be mediated by recombination signal sequence (RSS)-like elements present in the "recipient" VT15 gene. Among the many such elements on the inserted VT15 gene, which apparently met the requirement for an RSS with respect to nucleotide sequence, only two were observed in the actual rearrangements. This indicates that targeting of the recombination machinery involves sequences in addition to the RSS motifs as they have been characterized so far. In homozygous mutant mice, most B cells appeared to carry the intact VT15 gene on both mutant IgH alleles, although single-cell polymerase chain reaction revealed that silencing rearrangements occurred frequently in B cell progenitors in the bone marrow. This observation indicates that once silencing rearrangements are initiated in a cell, they involve both VT15 genes in most cases, reminiscent of normal DH-JH rearrangement. B cells which did not initiate such rearrangements develop to populate the peripheral B cell compartment.

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Section: Uniqueness Of T15i Mutant Mice In the Study Of The V Region mentioning

confidence: 91%

Rearrangement of upstream D_H and V_H genes to a rearranged immunoglobulin variable region gene inserted into the DQ52‐J_H region of the immunoglobulin heavy chain locus

1995

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“…At present, this is difficult to answer, because without specific molecular probes (3,20,21,32,38,57,72) or a strong phenotypic selection (2,11,26,27), cryptic rearrangements in a normal T-and B-cell population are effectively invisible. One would expect that natural selection has long since eliminated cryptic signals with a high probability of activating an oncogene through site-specific rearrangement.…”

Section: V(d)j Recombination Is An Obligatory Part Of T-and B-cell Dementioning

confidence: 99%

Cryptic Signals and the Fidelity of V(D)J Joining

Lewis

Agard

Suh

et al. 1997

Molecular and Cellular Biology

131

120

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V(D)J recombination is responsible for the de novo creation of antigen receptor genes in T-and B-cell precursors. To the extent that lymphopoiesis takes place throughout an animal's lifetime, recombination errors present an ongoing problem. One type of aberrant rearrangement ensues when DNA sequences resembling a V(D)J joining signal are targeted by mistake. This study investigates the type of sequence likely to be subject to mistargeting, the level of joining-signal function associated with these sequences, and the number of such cryptic joining signals in the genome.In a vertebrate, many millions of B and T cells are produced daily. A pivotal event in B-and T-cell differentiation is the assembly, through DNA recombination, of antigen receptor genes (reviewed in reference 43). Recombination is mediated by two key proteins, called RAG1 and RAG2, as well as an incompletely defined collection of other enzymes and factors (reviewed in references 28 and 56). During pre-B-cell and pre-T-cell development, DNA segments termed V, D, and J are assembled to form the variable exon of the expressed immunoglobulin (Ig) and T-cell receptor (TCR) genes. The joined gene segments encode the highly variable antigen-binding domain of the antigen receptor protein.V(D)J assembly is accomplished through DNA rearrangements that can encompass up to several megabases. The sequence motifs that serve as recognition elements for this process (joining signals) are surprisingly compact. A joining signal, found adjacent to every V, D, or J segment, is comprised of a heptamer (CACAGTG), a spacer (of 12 or 23 bp), and a nonamer (ACAAAAACC) (Fig. 1A). No sequence apart from the 28 (or 39)-bp joining signal motif is required for sitespecific recognition and recombination (reference 33 and references cited therein).Any V(D)J recombination event is normally an interaction between two gene segments, one of which possesses a 12-bp spacer (12-spacer) signal, and the other of which possesses a 23-bp spacer (23-spacer) signal. The molecular signature of V(D)J recombination is production of two types of junctions. One of these, the coding joint, is formed from the fusion of the two coding sequences (e.g., V and J), and the other, a signal joint, is formed from the corresponding joining signals. It is usual for a coding joint to have a small and variable degree of base loss and insertion at the point where the two coding elements connect, whereas the signal joint is typified by a precise fusion, heptamer to heptamer, of the two signals.Not surprisingly, DNA sequences that resemble an authentic joining signal (cryptic signals) are sometimes rearranged by mistake (first described in reference 36). The result is the production of recombinant junctions that are structurally analogous to coding joints and signal joints (Fig. 1) (17, 36). In this report, we take production of the characteristic junctions as the defining, diagnostic feature of a cryptic signal.Cryptic signals are seen at several of the Ig and TCR loci in both mice and humans and are active in re...

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“…24,25 In the past, some studies have suggested an association between oligoclonality and both poor outcome 13 and higher WBC, 26 not confirmed in recent studies. Two principle mechanisms have been implicated in the occurrence of multiple IGH gene rearrangements in ALL: (1) the persistent activity of the recombinase machinery in the immature B cells in ALL; [28][29][30] and (2) duplication of chromosome 14 (involving the chromosome band 14q32, the locus harboring the IGH) 13 although the link between these two events has not been fully explored to date. The former results in VH replacement to VNDNJ pre-existing rearrangements 31,32 or in an 'open-and-shut' VDJ modification as previously described in ALL patients.…”

Section: Introductionmentioning

confidence: 99%

Heterogeneity of VH–JH gene rearrangement patterns: an insight into the biology of B cell precursor ALL

et al. 2001

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Oligoclonal B cell proliferation, as defined by the presence of more than one leukemic clone, has been detected in approximately 20% to 30% of patients with acute lymphoblastic leukemia (ALL) using PCR or Southern blotting. An accurate assessment of these populations is required to avoid false negative measurements of minimal residual disease (MRD) in follow-up bone marrow (BM) samples of ALL patients. In this study, we analysed 29 ALL patients with two or more immunoglobulin heavy (IGH) chain gene rearrangements in the presentation samples using IGH fingerprinting PCR and sequence analysis. Thirty-nine (51%) of 76 sequences (from 15 patients), shared no VNDNJ homology (ie different CDR3 regions). In the remaining 14 patients, at least two related VH sequences were identified in each patient (identical DNJ sequences). Numerical abnormalities of chromosome 14 was detected in 10 patients. Eight patients were analysed at presentation and relapse. In four of them, expansion of a minor presentation-clone was detected at relapse while the major presentation clone disappeared, confirming 'subclonal evolution'. Finally, in our cohort of patients, the presence of related or unrelated IGH clones did not influence overall survival. Leukemia (2001) 15, 1527-1536.

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Immunoglobulin V gene replacement is caused by the intramolecular DNA deletion mechanism.

Cited by 31 publications

References 40 publications

Rearrangement of upstream D_H and V_H genes to a rearranged immunoglobulin variable region gene inserted into the DQ52‐J_H region of the immunoglobulin heavy chain locus

Rearrangement of upstream D_H and V_H genes to a rearranged immunoglobulin variable region gene inserted into the DQ52‐J_H region of the immunoglobulin heavy chain locus

Cryptic Signals and the Fidelity of V(D)J Joining

Heterogeneity of VH–JH gene rearrangement patterns: an insight into the biology of B cell precursor ALL

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Immunoglobulin V gene replacement is caused by the intramolecular DNA deletion mechanism.

Cited by 31 publications

References 40 publications

Rearrangement of upstream DH and VH genes to a rearranged immunoglobulin variable region gene inserted into the DQ52‐JH region of the immunoglobulin heavy chain locus

Rearrangement of upstream DH and VH genes to a rearranged immunoglobulin variable region gene inserted into the DQ52‐JH region of the immunoglobulin heavy chain locus

Cryptic Signals and the Fidelity of V(D)J Joining

Heterogeneity of VH–JH gene rearrangement patterns: an insight into the biology of B cell precursor ALL

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Rearrangement of upstream D_H and V_H genes to a rearranged immunoglobulin variable region gene inserted into the DQ52‐J_H region of the immunoglobulin heavy chain locus

Rearrangement of upstream D_H and V_H genes to a rearranged immunoglobulin variable region gene inserted into the DQ52‐J_H region of the immunoglobulin heavy chain locus