Molecular basis of heavy-chain class switching and switch region deletion in an Abelson virus-transformed cell line.

DePinho, Ronald A.; Kruger, Kelly; Andrews, Nancy C.; Lutzker, Stuart; Baltimore, David; Alt, Frederick W.

doi:10.1128/mcb.4.12.2905

Cited by 40 publications

(23 citation statements)

References 43 publications

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“…The ratio of productive and nonproductive transcripts was similar in all isotypes except ␣, indicating that in most of the CLL cells the two Ig H chain loci had switched to the same C H genes. This finding is in agreement with investigations in human and mouse B cell lines which have shown that the VDJ genes in both chromosomes frequently switch to genes that encode the same C H isotype (33,34).…”

Section: Discussionsupporting

confidence: 82%

IgM-producing chronic lymphocytic leukemia cells undergo immunoglobulin isotype-switching without acquiring somatic mutations.

Efremov¹,

Ivanovski²,

Batista³

et al. 1996

J. Clin. Invest.

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The malignant B cells in chronic lymphocytic leukemia (CLL) typically express low-density membrane IgM or IgM/ IgD. In vitro experiments have shown that the CLL cells can be induced to differentiate into cells that secrete immunoglobulin (Ig) and can occasionally undergo heavy (H) chain class switching. We now show that the CLL cells also undergo isotype-switching in vivo, since ␥ and/or ␣ H chain transcripts with identical FW3/CDR3/FW4 regions as the CLL transcripts were detected in all of the 13 investigated patients with IgM ϩ CLL. In most cases switching had occurred to ␣ 1 and ␥ 3, but CLL transcripts corresponding to the other ␥ chain isotypes were also detected. In one case both the productively and nonproductively rearranged allele were found to undergo H chain class switching. CLL ␥ transcripts were also present in surface IgG ϩ sorted B cells, demonstrating that a small subset of the CLL cells express membrane IgG. In addition, transcripts encoding secretory ␥ 2 and ␥ 3 H chains were detected in two cases, which suggests that some serum IgG could be produced by the leukemic clone. Analysis of sorted PBL showed that isotypeswitching occurs in CLL cells that express the CD5 antigen.

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Section: Discussionsupporting

confidence: 82%

IgM-producing chronic lymphocytic leukemia cells undergo immunoglobulin isotype-switching without acquiring somatic mutations.

Efremov¹,

Ivanovski²,

Batista³

et al. 1996

J. Clin. Invest.

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“…The location of the sites is taken from references 14-16, except for the Bcl I site, which was mapped in this study. The 5'-S.2b probe (5'S-Sy2b) is a 0.8-kb EcoRI-Bgl I fragment (17,18); the y2b cDNA probe is a Kpn I-BamHI fragment (19). normal switch variants with a y2b gene on the V2 allele.…”

Section: Methodsmentioning

confidence: 99%

Looping out and deletion mechanism for the immunoglobulin heavy-chain class switch.

Jäck

McDowell

Steinberg

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

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In the mouse pre-B-cell line 18-81, cells can switch production in vitro from immunoglobulin p chain to y2b chain. The gene encoding the y2b chain is created by a rearrangement of the I gene. This rearrangement always takes place within a homolog. In cells with a y2b gene, most of the time the gene segment encoding the constant region of the ,u chain is deleted, but often the rearrangement leads to cells that produce no immunoglobulin, and all DNA sequences are retained. The latter result is due to an inversion. Inversions exclude the unequal sister chromatid exchange model of the heavy-chain class switch. Looping out is an intermediate step in the process of generating an inversion. Our findings demonstrate that the switch rearrangement occurs by looping out and deletion.When injected with an antigen, higher vertebrates can respond by producing antibodies that are immunoglobulins of various classes. These classes differ in the heavy (H) chain that combines with the light chain to form the complete immunoglobulin molecule. In the mouse, the early immune response is dominated by IgM, which contains the H chain ,, and the later immune response is dominated by IgG3, IgGl, IgG2b, IgG2a, IgA, and (rarely) IgE, which contain the H chains y3, yl, y2b, y2a, a, and E, respectively. At the genetic level, the gene encoding the ,u chain consists of a variable (V)-region gene segment, which has been somatically assembled from one each of the VH, diversity (D), and joining (JH) segments, and the nearby C,,, gene segment, which encodes the constant (C) region of the ,u chain. Upon H-chain switching, which occurs within a clone derived from a committed lymphocyte (1, 2), the V region remains the same, but the C region changes. C,, is replaced by C,3, C 11 C,,2b, CE, or C., which are the C-region gene segments of the respective chains and are closely linked to C,,, in that order (reviewed in refs. 3 and 4).This rearrangement event generally results in deletion of the DNA sequences between a site within the intron 5' to C,, and a site within the intron 5' to the particular C-region gene segment that is to be expressed.

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“…Examination of a large series of these isolates has shown that while all have begun or completed VHDJH joining 5' of Cp,u less than 5% have rearranged either K or A L-chain genes (3), reinforcing their relationship to normal pre-B lymphocytes. Several groups have described rare clones that undergo isotype switching accompanied by deletion, a phenomenon normally associated with more mature cells (10,14). Other rare clones (less than 5% of all isolates) express enhanced levels of ,.…”

Section: Discussionmentioning

confidence: 99%

Abelson virus potentiates long-term growth of mature B lymphocytes.

Serunian¹,

Rosenberg²

1986

Mol. Cell. Biol.

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Abelson murine leukemia virus (A-MuLV) infection of mouse bone marrow cells usually leads to transformation of pre-B cells. However, when the environment is modified by the continuous presence of lipopolysaccharide (LPS), two novel types of membrane immunoglobulin (m1g)-positive B cell lines are generated. Because the cells which give rise to these cell lines copurify with mlg-positive bone marrow cells, the cell lines arise as a result of A-MuLV interaction with a new type of in vitro target cell. The cell lines generated fall into two groups which differ in several phenotypic characteristics. Group 1 cells are more differentiated than the typical pre-B cell transformant in that they synthesize mIgM and appear to resemble virgin B cells. The group 1 cells do not secrete immunoglobulin and are independent of LPS for growth. In addition, these cell lines synthesize the Abelson P160 protein, contain integrated abl proviral DNA, and are highly tumorigenic in syngeneic animals. The group 2 cell lines differ markedly from both the group 1 cells and from typical, pre-B cell A-MuLV transformants. These cells are mIgG positive and secrete large amounts of immunoglobulin into the culture medium. The cell lines are comprised of both adherent and nonadherent cells and do not synthesize P160 or contain integrated v-abl sequences. The group 2 cels are nontumorigenic in syngeneic animals and require LPS for growth and viability. Both types of cells have remained in culture for over 2 years with no changes in their phenotypic characteristics. This A-MuLV infection system and the novel mlg-positive cell lines may serve as useful models for studying biochemical and molecular properties of mature B cells.

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Molecular basis of heavy-chain class switching and switch region deletion in an Abelson virus-transformed cell line.

Cited by 40 publications

References 43 publications

IgM-producing chronic lymphocytic leukemia cells undergo immunoglobulin isotype-switching without acquiring somatic mutations.

IgM-producing chronic lymphocytic leukemia cells undergo immunoglobulin isotype-switching without acquiring somatic mutations.

Looping out and deletion mechanism for the immunoglobulin heavy-chain class switch.

Abelson virus potentiates long-term growth of mature B lymphocytes.

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