Homologous chromosome recombination generating immunoglobulin allotype and isotype switch variants.

Kipps, Thomas J.; Herzenberg, L A

doi:10.1002/j.1460-2075.1986.tb04208.x

Cited by 32 publications

(13 citation statements)

References 47 publications

(28 reference statements)

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“…Even though 4A5 binds to ROR1 with nearly an order of magnitude higher affinity than D10, this mAb is less effective in inhibiting the growth of ROR1 × TCL1 leukemia cells in vivo. It appears unlikely that this is due to differences in antibody subclass, as the heavy chain constant region isotype of D10 or 4A5 is IgG2 a or IgG2 b , respectively, each of which could direct antibody-dependent cellular cytotoxicity (36)(37)(38). Instead we hypothesize that the activity of each mAb also may be influenced by how each mAb binds to ROR1, which The bars represent the mean number for each group ± SEM; n = 3; *P < 0.05, **P < 0.01, compared with the mIgG group, as calculated using the Student t test.…”

Section: Discussionmentioning

confidence: 99%

ROR1 can interact with TCL1 and enhance leukemogenesis in Eµ-TCL1 transgenic mice

Widhopf¹,

Cui²,

Ghia³

et al. 2013

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

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Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncoembryonic antigen found on chronic lymphocytic leukemia (CLL) B cells, but not on normal adult tissues. We generated transgenic (Tg) mice with human ROR1 regulated by the murine Ig promoter/enhancer. In contrast to nontransgenic littermates, such animals had B-cell-restricted expression of ROR1 and could develop clonal expansions of ROR1 bright CD5 + B220 low B cells resembling human CLL at ≥15 mo of age. Because immune-precipitation and mass spectrometry studies revealed that ROR1 could complex with T-cell leukemia 1 (TCL1) in CLL, we crossed these animals with Eμ-TCL1-Tg (TCL1) mice. Progeny with both transgenes (ROR1 × TCL1) developed CD5 + B220low B-cell lymphocytosis and leukemia at a significantly younger median age than did littermates with either transgene alone. ROR1 × TCL1 leukemia B cells had higher levels of phospho-AKT than TCL1 leukemia cells and expressed high levels of human ROR1, which we also found complexed with TCL1. Transcriptome analyses revealed that ROR1 × TCL1 leukemia cells had higher expression of subnetworks implicated in embryonic and tumor-cell proliferation, but lower expression of subnetworks involved in cell-cell adhesion or cell death than did TCL1 leukemia cells. ROR1 × TCL1 leukemia cells also had higher proportions of K i -67-positive cells, lower proportions of cells undergoing spontaneous apoptosis, and produced more aggressive disease upon adoptive transfer than TCL1 leukemia cells. However, treatment with an anti-ROR1 mAb resulted in ROR1 down-modulation, reduced phospho-AKT, and impaired engraftment of ROR1 × TCL1 leukemia cells. Our data demonstrate that ROR1 accelerates development/progression of leukemia and may be targeted for therapy of patients with CLL. mouse model | monoclonal antibody | AKT | immune therapy R eceptor tyrosine kinase-like orphan receptor 1 (ROR1) is a type 1 tyrosine kinase surface protein expressed on chronic lymphocytic leukemia (CLL) B cells, but not on nonmalignant postpartum tissues (1). Expression of ROR1 ordinarily is confined to early embryogenesis, where it contributes to organogenesis (2-4). However, ROR1 is not detected on postpartum tissues, including hematopoietic stem cells, except on a small subset of B-cell precursors, called hematogones (5). We and others have found ROR1 expressed on the neoplastic cells of patients with CLL (1, 6, 7), other B-cell lymphomas (8), acute leukemias (5, 9), and on any one of a variety of solid tumors (10-13). However, it still is uncertain whether ROR1 plays a role in cancer development and/or disease progression.ROR1 has an extracellular domain that is essential for ligand binding and potentially for intracellular signaling (14). Although it has a putative kinase domain, ROR1 might function as a pseudokinase, serving instead as a cofactor for other signaling proteins (13). We found that ROR1 could serve as a receptor for Wnt5a, which could provide a survival/growth signal to CLL cells from the microenvironment (1). Also, ROR1 could enh...

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Section: Discussionmentioning

confidence: 99%

ROR1 can interact with TCL1 and enhance leukemogenesis in Eµ-TCL1 transgenic mice

Widhopf¹,

Cui²,

Ghia³

et al. 2013

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

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“…However, there is little evidence that the normal switching mechanism in mice might promote interchromosomal recombinations; only one such possible event has been reported (37), found in a transformed cell line that undergoes switching during cell culture. If, as seems more likely, transgene switching is a two-step process that begins with an interchromosomal homology-based recombination event, then our results indicate that this homologous recombination does not require Rad54.…”

Section: Discussionmentioning

confidence: 99%

Gene Conversion-Like Sequence Transfers Between Transgenic Antibody V Genes Are Independent of RAD54

D'Avirro

Truong

Luong

et al. 2002

The Journal of Immunology

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Homology-based Ig gene conversion is a major mechanism for Ab diversification in chickens and the Rad54 DNA repair protein plays an important role in this process. In mice, although gene conversion appears to be rare among endogenous Ig genes, Ab H chain transgenes undergo isotype switching and gene conversion-like sequence transfer processes that also appear to involve homologous recombination or gene conversion. Furthermore, homology-based DNA repair has been suggested to be important for somatic mutation of endogenous mouse Ig genes. To assess the role of Rad54 in these mouse B cell processes, we have analyzed H chain transgene isotype switching, sequence transfer, and somatic hypermutation in mice that lack RAD54. We find that Rad54 is not required for either transgene switching or transgene hypermutation. Furthermore, even transgene sequence transfers that are known to require homology-based recombinations are Rad54 independent. These results indicate that mouse B cells must use factors for promoting homologous recombination that are distinct from the Rad54 proteins important in homology-based chicken Ab gene recombinations. Our findings also suggest that mouse H chain transgene sequence transfers might be more closely related to an error-prone homology-based somatic hypermutational mechanism than to the hyperconversion mechanism that operates in chicken B cells.

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“…Thus, both in vivo and in vitro somatic cells were shown to undergo recombinational events, resulting in the emergence of homozygous cells from wild-type heterozygous cells. Recombination between homologous chromosomes has been described in hybrids of CHO cells (4) and most recently in some instances of immunoglobulin class switching (6).…”

Section: Discussionmentioning

confidence: 99%

“…Although recombination between homologous chromosomes in somatic mammalian cells has been difficult to demonstrate (1,2), several recent reports (3)(4)(5)(6) have shown that it can occur. Cavenee et al (3) described a human retinoblastoma in which, following a recombination between the homologous chromosome 13s, the Rb-i and distal loci had become homozygous while proximal loci were still heterozygous.…”

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confidence: 99%

Mitotic recombination between homologous chromosomes generates H-2 somatic cell variants in vitro.

Potter¹,

Zeff²,

Frankel³

et al. 1987

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

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A spontaneously arising variant clone that does not express the H-2Dd and H-2Ld molecules was isolated by immunoselection from an (H-2b X H-2d)F1 cell line. This variant clone expresses H-2Kb, H-2Db, and H-2Kd molecules. Southern blot analysis demonstrated that the variant was heterozygous at the H-2K, I, and S loci but had lost the H-2Dd and H-2Ld genes. Karyotype analysis showed that neither of the chromosome 17s in the variant had undergone detectable deletions. Quantitative Southern blot analysis demonstrated that the variant had two copies of the H-2Db gene, whereas the parental cell line had one copy of H-2Db. The loss of the H-2Ld and H-2Dd genes, accompanied by the attainment of homozygosity at H-2Db, is consistent with a recombination between the two chromosome 17 homologues. We conclude that although mitotic recombination between homologues has been difficult to demonstrate, it may not be infrequent and may account for the development of mutant genotypes in somatic cells in vitro. Such a mechanism occurring in vivo could result in the emergence of cells that are homozygous for deleterious alleles even though the individual may be constitutionally heterozygous.

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Homologous chromosome recombination generating immunoglobulin allotype and isotype switch variants.

Cited by 32 publications

References 47 publications

ROR1 can interact with TCL1 and enhance leukemogenesis in Eµ-TCL1 transgenic mice

ROR1 can interact with TCL1 and enhance leukemogenesis in Eµ-TCL1 transgenic mice

Gene Conversion-Like Sequence Transfers Between Transgenic Antibody V Genes Are Independent of RAD54

Mitotic recombination between homologous chromosomes generates H-2 somatic cell variants in vitro.

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