Spatial genome organization in the formation of chromosomal translocations

Meaburn, Karen J.; Misteli, Tom; Soutoglou, Evi

doi:10.1016/j.semcancer.2006.10.008

Cited by 182 publications

(157 citation statements)

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“…Two hypotheses have been proposed to explain how translocations arise: the ''contact-first'' model postulates that chromosome fibers have to colocalize at the time of DNA damage (9), whereas the ''breakage-first'' model states that broken chromosome ends can move in the nuclear space to find their translocation partner (10). Although formal evidence is currently lacking, recent data favor the contact-first model as the underlying mechanism required for formation of translocations in mammalian cells (8,9,(11)(12)(13).Here, we set out to study the mechanism of translocation formation and of ALCL transformation by the analysis of ALCL either carrying or lacking the characteristic t(2;5). We describe a number of deregulated genes surrounding the breakpoint regions on chromosomes 5 and 2 in both ALCL cells with and without the characteristic translocation.…”

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Gene deregulation and spatial genome reorganization near breakpoints prior to formation of translocations in anaplastic large cell lymphoma

Mathas

Kreher

Meaburn

et al. 2009

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

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Although the identification and characterization of translocations have rapidly increased, little is known about the mechanisms of how translocations occur in vivo. We used anaplastic large cell lymphoma (ALCL) with and without the characteristic t(2;5)(p23;q35) translocation to study the mechanisms of formation of translocations and of ALCL transformation. We report deregulation of several genes located near the ALCL translocation breakpoint, regardless of whether the tumor contains the t(2;5). The affected genes include the oncogenic transcription factor Fra2 (located on 2p23), the HLH protein Id2 (2p25), and the oncogenic tyrosine kinase CSF1-receptor (5q33.1). Their up-regulation promotes cell survival and repression of T cellspecific gene expression programs that are characteristic for ALCL. The deregulated genes are in spatial proximity within the nuclear space of t(2;5)-negative ALCL cells, facilitating their translocation on induction of double-strand breaks. These data suggest that deregulation of breakpoint-proximal genes occurs before the formation of translocations, and that aberrant transcriptional activity of genomic regions is linked to their propensity to undergo chromosomal translocations. Also, our data demonstrate that deregulation of breakpoint-proximal genes has a key role in ALCL.cancer genetics ͉ signal transduction ͉ nuclear architecture ͉ lymphomatoid papulosis B alanced chromosomal translocations are a hallmark of cancer cells, and are thought to be important, if not causal, for hematopoietic and mesenchymal tumorigenesis (1). At the molecular level, translocations generally result in either altered expression of genes located directly at a breakpoint, or in fusion of genes located at the 2 breakpoints (1). In most cases, the affected genes are transcription factors or tyrosine kinases, and the translocation generally leads to their inactivation or constitutive activation. This defect often causes inhibition of differentiation or uncontrolled proliferation. Nevertheless, translocations are, at least in some cases, not sufficient to fully transform cells, because chromosomal disease-associated translocations are present in healthy individuals (2), and transgenic mice expressing known tumor fusion proteins do not spontaneously develop tumors in most cases (1, 2).The translocation t(2;5)(p23;q35) is characteristic for anaplastic large cell lymphoma (ALCL), a subgroup of peripheral T cell lymphomas (TCL) (3, 4). By fusion of the 5Ј oligomerization domain of the nucleophosmin (NPM1) gene (located on 5q35) with the 3Ј anaplastic lymphoma kinase (ALK) tyrosine kinase domain (2p23), this translocation results in a NPM-ALK fusion protein with constitutive activation of the ALK kinase (3). Several questions regarding the pathogenesis of ALCL are unresolved. First, in Ϸ40% of systemic ALCL, the translocation t(2;5) is not present (4), suggesting yet unknown alternative mechanisms of transformation. Second, the expression of NPM-ALK per se might not be sufficient for malignant transformation to ALC...

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confidence: 99%

“…Although the identification and characterization of translocations have rapidly increased, little is known about how translocations occur in vivo (1,8). Obviously, double-strand breaks (DSBs) of involved chromosomes have to occur, and broken ends have to meet each other in the nucleus.…”

mentioning

confidence: 99%

Gene deregulation and spatial genome reorganization near breakpoints prior to formation of translocations in anaplastic large cell lymphoma

Mathas

Kreher

Meaburn

et al. 2009

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

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101

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“…These are suggested to result from failure of genome maintenance and DNA repair machineries, which also depend on interphase chromosome architecture [19]. On the other hand, specific chromosome positioning (intermingling Visualization of interphase chromosomes of chromosome territories) is considered as a mechanism of promoting cancer-causing interchromosomal translocations [8,10,11,18]. Furthermore, interphase chromosome associations (somatic pairing) seem to be involved in regulation of transcriptional activity within specific chromosomal regions including imprinted genomic loci, known to be linked to hereditary diseases and cancer [20].…”

Section: Nuclear Genome/chromosome Organization and Diseasementioning

confidence: 99%

“…Using ICS-MCB, chromosome architecture was evaluated in some tissues at "subchromosomal" resolution and specific positioning of chromosomal loci was shown to be linked to generation and behavior of rearranged chromosomes in interphase [8][9][10]. Interestingly, specific chromosome positioning was previously suggested to predispose to cancer-causing chromosomal aberrations [11]. Unfortunately, convincing proofs were not obtained because the data were usually acquired by techniques painting chromosome territories without an integral view of the whole chromosome.…”

Section: Introductionmentioning

confidence: 99%

To see an interphase chromosome or: How a disease can be associated with specific nuclear genome organization

Iourov¹

2012

Biodiscovery

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The last hierarchical level of cellular genome organization is the spatial arrangement of chromosomes within the nuclear space. Despite of high regulatory potential and functional implications, issues concerning nuclear organization at chromosomal level are rarely addressed because of limitations in visualizing interphase chromosomes. The problem is especially seen when an attempt to associate specific patterns of nuclear genome organization with a pathological condition is made. Fortunately, advances in molecular cytogenetics have provided for a solution to visualize chromosomes in interphase nuclei at molecular resolution. A study in this issue of BioDiscovery shows the way of how to identify interphase chromosome architecture at molecular resolutions and demonstrates the involvement of specific nuclear genome organization in generating a cancercausing chromosomal aberration (translocation between chromosomes 8 and 21 in acute myelogenous leukemia). Authors' findings suggest interphase molecular cytogenetic techniques (i.e. interphase chromosome-specific multicolor banding or ICS-MCB) to be required to perform studies regarding nuclear genome organization at chromosomal level and its role in disease pathogenesis.

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“…Furthermore, non-random positioning in interphase nuclei is known to be of importance for genomic stability and formation of chromosome aberrations. Tissue specificity of chromosomal translocations could be due to tissue specific genome organization [5][6], and a positive correlation between spatial proximity of chromosomes/ genes in interphase nuclei and translocation frequencies was shown [5][6][7][8][9][10]. Three-dimensional (3D) fluorescence in situ hybridization (FISH) analysis became a major tool 3D-positioning of chromosomes 8 and 21 in AML for studying this higher order chromatin organization in the cell nucleus [4; 11-15].…”

Section: Introductionmentioning

confidence: 99%

Does positioning of chromosomes 8 and 21 in interphase drive t(8;21) in acute myelogenous leukemia?

Lier¹,

Junker²,

Kempf³

et al. 2012

Biodiscovery

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The impact of chromosome architecture in the formation of chromosome aberrations is a recent finding of interphase directed molecular cytogenetic studies. There evidence was provided that disease specific chromosomal translocations could be due to tissue specific genomic organization. In a recent small pilot study using three-dimensional interphase fluorescence in situ hybridization, we showed that there might be a specific chromosome positioning in myeloid bone marrow cells, i.e. a co-localization of chromosomes 8 and 21. Here we could substantiate this finding in overall 21 studied cases with acute myeloid leukemia (AML) that there is even a co-localization of the genes AML1 and ETO. This finding led to the suggestion that a specific interphase architecture of myeloid bone marrow cells might promote the typical t(8;21)(q22;q22) leading to AML-M2.

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Spatial genome organization in the formation of chromosomal translocations

Cited by 182 publications

References 132 publications

Gene deregulation and spatial genome reorganization near breakpoints prior to formation of translocations in anaplastic large cell lymphoma

Gene deregulation and spatial genome reorganization near breakpoints prior to formation of translocations in anaplastic large cell lymphoma

To see an interphase chromosome or: How a disease can be associated with specific nuclear genome organization

Does positioning of chromosomes 8 and 21 in interphase drive t(8;21) in acute myelogenous leukemia?

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