Oncogenic
            <i>Myc</i>
            translocations are independent of chromosomal location and orientation of the immunoglobulin heavy chain locus

Spehalski, Elizabeth I.; Kovalchuk, Alexander L.; Collins, John T.; Liang, Guanxiang; Dubois, Wendy; Morse, Herbert C.; Ferguson, David O.; Casellas, Rafael; Dunnick, Wesley A.

doi:10.1073/pnas.1202882109

Cited by 10 publications

(9 citation statements)

References 43 publications

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“…Indeed, recent large-scale studies have confirmed this, demonstrating that translocations tend to occur between sites that are spatially juxtaposed in the nucleus (Hakim et al, 2012;Zhang et al, 2012). Arguing in favor of movement, on the other hand, Spehalski et al (2012) showed that Myc-Igh translocations in mouse cells occur at the same frequency regardless of where the Igh is placed in the genome. Understanding what regulates DSB movement and its impact on specific recombination events is clearly important for understanding oncogenic translocations.…”

Section: Chromatin Movement Driven By Nucleosome Remodelingmentioning

confidence: 90%

Chromatin Movement in the Maintenance of Genome Stability

Dion

Gasser

2013

Cell

201

179

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Mechanistic analyses based on improved imaging techniques have begun to explore the biological implications of chromatin movement within the nucleus. Studies in both prokaryotes and eukaryotes have shed light on what regulates the mobility of DNA over long distances. Interestingly, in eukaryotes, genomic loci increase their movement in response to double-strand break induction. Break mobility, in turn, correlates with the efficiency of repair by homologous recombination. We review here the source and regulation of DNA mobility and discuss how it can both contribute to and jeopardize genome stability.

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Section: Chromatin Movement Driven By Nucleosome Remodelingmentioning

confidence: 90%

Chromatin Movement in the Maintenance of Genome Stability

Dion

Gasser

2013

Cell

201

179

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“…Cell lines bearing Myc translocations with either the ARS /Igh 11 transgene (schematics of the molecular structure of the transgene and Myc / Igh-TG translocations are presented on Supplementary Figure 6 ) or endogenous Igh [ 28 ] were transduced with Cre-ER-expressing or empty retroviral vectors (EV) [ 29 ]. 4-OHT treatment triggers nuclear translocation of Cre-ER and recombination of loxP sites in target DNA resulting in complete deletion of hs3a, hs1,2, hs3b and hs4 enhancers.…”

Section: Resultsmentioning

confidence: 99%

3’Ighenhancers hs3b/hs4 are dispensable forMycderegulation in mouse plasmacytomas with T(12;15) translocations

Kovalchuk

Sakai

et al. 2018

Oncotarget

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Myc-deregulating T(12;15) chromosomal translocations are the hallmark cytogenetic abnormalities of murine plasmacytomas (PCTs). In most PCTs, the immunoglobulin heavy chain (Igh) locus is broken between the Eμ enhancer and the 3’ regulatory region (3’RR), making the latter the major candidate for orchestrating Myc deregulation. To elucidate the role of the Igh3’RR in tumorigenesis, we induced PCTs in Bcl-xL-transgenic mice deficient for the major Igh3’RR enhancer elements, hs3b and hs4 (hs3b-4-/-). Contrary to previous observations using a mouse lymphoma model, which showed no tumors with peripheral B-cell phenotype in hs3b-4-/- mice, these animals developed T(12;15)-positive PCTs, although with a lower incidence than hs3b-4+/+ (wild-type, WT) controls. In heterozygous hs3b-4+/- mice there was no allelic bias in targeting Igh for T(12;15). Molecular analyses of Igh/Myc junctions revealed dominance of Sμ region breakpoints versus the prevalence of Sγ or Sα in WT controls. Myc expression and Ig secretion in hs3b-4-/- PCTs did not differ from WT controls. We also evaluated the effect of a complete Igh3’RR deletion on Myc expression in the context of an established Igh/Myc translocation in ARS/Igh11-transgenic PCT cell lines. Cre-mediated deletion of the Igh3’RR resulted in gradual reduction of Myc expression, loss of proliferative activity and increased cell death, confirming the necessity of the Igh3’RR for Myc deregulation by T(12;15).

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“…On the other hand, transcription at the IGH@ locus is controlled by enhancers elements spread out as wide as 2.5 Mb of the locus [12], and it contains regulatory elements necessary not only for MYC activation but also the promotion of translocation [13]. CMA detected a 455 Kb copy number loss on chromosome band 14q32.2, not detected by FISH since the probe used was outside of this region.…”

Section: Discussionmentioning

confidence: 99%

“…The IGH transcription factory, about 2.5 Mb in size [12], localizes the regulatory elements for MYC deregulation and variable regions that promote translocation [13]. The IGH@ locus, is a hotspot for recombination and mutation of immunoglobulin genes during B-cell maturation, processes that usually promote translocations with oncogenic potential [11].…”

Section: Introductionmentioning

confidence: 99%

Atypical rearrangement involving 3′-IGH@ and a breakpoint at least 400 Kb upstream of an intact MYC in a CLL patient with an apparently balanced t(8;14)(q24.1;q32) and negative MYC expression

et al. 2013

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The t(8;14)(q24.1;q32), the cytogenetic hallmark of Burkitt’s lymphoma, is also found, but rarely, in cases of chronic lymphocytic leukemia (CLL). Such translocation typically results in a MYC-IGH@ fusion subsequently deregulating and overexpressing MYC on der 14q32. In CLL, atypical rearrangements resulting in its gain or loss, within or outside of IGH@ or MYC locus, have been reported, but their clinical significance remains uncertain. Herein, we report a 67 year-old male with complex cytogenetic findings of apparently balanced t(8;14) and unreported complex rearrangements of IGH@ and MYC loci. His clinical, morphological and immunophenotypic features were consistent with the diagnosis of CLL.Interphase FISH studies revealed deletions of 11q22.3 and 13q14.3, and an extra copy of IGH@, indicative of rearrangement. Karyotype analysis showed an apparently balanced t(8;14)(q24.1;q32). Sequential GPG-metaphase FISH studies revealed abnormal signal patterns: rearrangement of IGH break apart probe with the 5’-IGH@ on derivative 8q24.1 and the 3’-IGH@ retained on der 14q; absence of MYC break apart-specific signal on der 8q; and, the presence of unsplit 5’-MYC-3’ break apart probe signals on der 14q. The breakpoint on 8q24.1 was found to be at least 400 Kb upstream of 5’ of MYC. In addition, FISH studies revealed two abnormal clones; one with 13q14.3 deletion, and the other, with concurrent 11q deletion and atypical rearrangements. Chromosome microarray analysis (CMA) detected a 7.1 Mb deletion on 11q22.3-q23.3 including ATM, a finding consistent with FISH results. While no significant copy number gain or loss observed on chromosomes 8, 12 and 13, a 455 Kb microdeletion of uncertain clinical significance was detected on 14q32.33. Immunohistochemistry showed co-expression of CD19, CD5, and CD23, positive ZAP-70 expression and absence of MYC expression. Overall findings reveal an apparently balanced t(8;14) and atypical complex rearrangements involving 3’-IGH@ and a breakpoint at least 400 Kb upstream of MYC, resulting in the relocation of the intact 5’-MYC-3’ from der 8q, and apposition to 3’-IGH@ at der 14q. This case report provides unique and additional cytogenetic data that may be of clinical significance in such a rare finding in CLL. It also highlights the utility of conventional and sequential metaphase FISH in understanding complex chromosome anomalies and their association with other clinical findings in patients with CLL. To the best of our knowledge, this is the first CLL reported case with such an atypical rearrangement in a patient with a negative MYC expression.

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Oncogenic Myc translocations are independent of chromosomal location and orientation of the immunoglobulin heavy chain locus

Cited by 10 publications

References 43 publications

Chromatin Movement in the Maintenance of Genome Stability

Chromatin Movement in the Maintenance of Genome Stability

3’Ighenhancers hs3b/hs4 are dispensable forMycderegulation in mouse plasmacytomas with T(12;15) translocations

Atypical rearrangement involving 3′-IGH@ and a breakpoint at least 400 Kb upstream of an intact MYC in a CLL patient with an apparently balanced t(8;14)(q24.1;q32) and negative MYC expression

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