The Origin of B Cell Recurrent Chromosomal Translocations: Proximity versus DNA Damage

Casellas, Rafael; Resch, Wolfgang; Hakim, Ofir; Nussenzweig, Michel C.

doi:10.1016/j.molcel.2013.07.020

Cited by 5 publications

(4 citation statements)

References 9 publications

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“…There is no evidence in human lymphoid translocations that proximity is an important factor. Rather, the DNA breakage process appears to be the rate-limiting step, and studies in murine systems support this interpretation 83 .…”

Section: Future Questionsmentioning

confidence: 99%

Mechanisms of human lymphoid chromosomal translocations

2016

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Analysis of human chromosomal translocation sequence locations has yielded valuable clues about the mechanism of the translocations and their timing. Biochemical work on the mechanisms of DNA breakage and rejoining permits formulation of a detailed model of the human chromosomal translocation process in lymphoid neoplasms. Most human lymphomas are derived from B cells in which the break is initiated by activation-induced deaminase (AID). The partner locus in many cases is located at one of the antigen receptor loci, and this break is generated by the RAG complex or by AID. After breakage, the joining process typically occurs by nonhomologous DNA end joining (NHEJ). Some of the insights into this mechanism also apply to nonlymphoid neoplasms.

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Section: Future Questionsmentioning

confidence: 99%

Mechanisms of human lymphoid chromosomal translocations

2016

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“…However, 4C analysis by the Skok group of the Igh gene came to the opposite conclusion; they found that a very strong correlation exists between the genes that coassociate with Igh in normal cells and those that have a predisposition to translocate (42). The differences are being hotly debated and largely relate to how the bioinformatics analyses have been carried out (43,44). Input from other bioinformaticians with expertize in genome organization and handling such datasets would be highly beneficial to help resolve these differences of interpretation.…”

Section: Proximity Transcription and Chromosomal Translocationsmentioning

confidence: 99%

Molecular Pathways: Transcription Factories and Chromosomal Translocations

Osborne

2014

Clinical Cancer Research

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The mammalian nucleus is a highly complex structure that carries out a diverse range of functions such as DNA replication, cell division, RNA processing, and nuclear export/import. Many of these activities occur at discrete subcompartments that intersect with specific regions of the genome. Over the past few decades, evidence has accumulated to suggest that RNA transcription also occurs in specialized sites, called transcription factories, that may influence how the genome is organized. There may be certain efficiency benefits to cluster transcriptional activity in this way. However, the clustering of genes at transcription factories may have consequences for genome stability, and increase the susceptibility to recurrent chromosomal translocations that lead to cancer. The relationships between genome organization, transcription, and chromosomal translocation formation will have important implications in understanding the causes of therapy-related cancers. Clin Cancer Res; 20(2); 296-300. Ó2013 AACR.

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“…Off-target activity of the diversification enzymes may provide the initial step in the translocation process through the formation of DNA double-strand breaks in genes spatially proximal to IGH (Peters and Storb, 1996;Fukita et al, 1998;Pasqualucci et al, 2001;Schrader et al, 2007;Liu et al, 2008;Robbiani et al, 2008;Tsai et al, 2008;Hu et al, 2015). Casellas et al suggest that the translocation frequency of AID targets is determined by the amount of enzyme-mediated DNA damage, and although necessary, not predicted by proximity to IGH (Casellas et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

FGFR3 preferentially colocalizes with IGH in the interphase nucleus of multiple myeloma patient B‐cells when FGFR3 is located outside of CT4

Martin

Harizanova

Mai

et al. 2016

Genes Chromosomes & Cancer

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Many B-cell malignancies are characterized by chromosomal translocations involving IGH and a proto-oncogene. For translocations to occur, spatial proximity of translocation-prone genes is necessary. Currently, it is not known how such genes are brought into proximity with one another. Although decondensed chromosomes occupy definitive, non-random spaces in the interphase nucleus known as chromosome territories (CTs), chromatin at the edges of CTs can intermingle, and specific genomic regions from some chromosomes have been shown to "loop out" of their respective CTs. This extra-territorial positioning of specific genomic regions may provide a mechanism whereby translocation-prone genes are brought together in the interphase nucleus. FGFR3 and MAF recurrently participate in translocations with IGH at different frequencies. Using 3D, 4-color FISH, and 3D analysis software, we show frequent extra-territorial positioning of FGFR3 and significantly less frequent extra-territorial positioning of MAF. Frequent extra-territorial positioning may be characteristic of FGFR3 in B-cells from healthy adult donors and non-malignant B-cells from patients, but not in hematopoietic stem cells from patients with translocations. The frequency of extra-territorial positioning of FGFR3 and MAF in B-cells correlates with the frequency of translocations in the patient population. Most importantly, in patient B-cells, we demonstrate a significant proportion of extra-territorial FGFR3 participating in close loci pairs and/or colocalizing with IGH. This preliminary work suggests that in patient B-cells, extra-territorial positioning of FGFR3 may provide a mechanism for forming close loci pairs and/or colocalization with IGH; indirectly facilitating translocation events involving these two genes. © 2016 Wiley Periodicals, Inc.

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The Origin of B Cell Recurrent Chromosomal Translocations: Proximity versus DNA Damage

Cited by 5 publications

References 9 publications

Mechanisms of human lymphoid chromosomal translocations

Mechanisms of human lymphoid chromosomal translocations

Molecular Pathways: Transcription Factories and Chromosomal Translocations

FGFR3 preferentially colocalizes with IGH in the interphase nucleus of multiple myeloma patient B‐cells when FGFR3 is located outside of CT4

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