Jumping translocations, a novel finding in chronic lymphocytic leukaemia

Miller, Cecelia; Stephens, Deborah M.; Ruppert, Amy S.; Racke, Frederick; McFaddin, Andrew; Breidenbach, H; Lin, Huey; Waller, Kathy V.; Bannerman, Tammy L.; Jones, Jeffrey A.; Woyach, Jennifer A.; Andritsos, Leslie A.; Maddocks, Kami J.; Zhao, Weiqiang; Lozanski, Gerard; Flynn, Joseph M.; Byrd, John C.; Heerema, Nyla A.

doi:10.1111/bjh.13422

Cited by 9 publications

(4 citation statements)

References 38 publications

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“…However, the cases with recipient chromosomes and a breakpoint in the telomeric region did not have a pathogenic variant in the TP53 gene and/or a loss of the 17p13 locus ( TP53 ). Miller et al showed that 23 of the 26 CLL patients with jumping translocations (88%) had a loss of TP53 and that the recipient breakpoints most frequently occurred in the centromeric region and very rarely in the telomeric region. TP53 is known as the guardian of the genome—for example, TP53 is involved in arresting the cell cycle or inducing apoptosis in damaged cells .…”

Section: Discussionmentioning

confidence: 99%

Jumping translocations: Short telomeres or pathogenic TP53 variants as underlying mechanism in acute myeloid leukemia and myelodysplastic syndrome?

Behrens

Thomay

Hagedorn

et al. 2019

Genes Chromosomes & Cancer

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Chromosomal rearrangements involving one donor chromosome and two or more recipient chromosomes are called jumping translocations. To date only few cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with jumping translocations have been described and the underlying mechanisms remain unclear. Here, we analyzed 11 AML and 5 MDS cases with jumping translocations. The cases were analyzed by karyotyping, FISH, telomere length measurement, and next-generation sequencing with an AML/MDS gene panel.Cases with jumping translocations showed significantly (P < .01) shorter telomeres in comparison to healthy age-matched controls. Additional neo-telomeres were found in two cases. In total, eight cases showed recipient chromosomes with a breakpoint in the centromeric region all of them harboring a pathogenic variant in the TP53 gene (n = 6) and/or a loss of TP53 (n = 5). By contrast, no pathogenic variant or loss of TP53 was identified in the six cases showing recipient chromosomes with a breakpoint in the telomeric region. In conclusion, our results divide the cohort of AML and MDS cases with jumping translocations into two groups: the first group with a telomeric breakpoint of the recipient chromosome is characterized by short telomeres and a possibly telomere-based mechanism of chromosomal instability formation. The second group with a centromeric breakpoint of the recipient chromosome is defined by mutation and/or loss of TP53. We, therefore, assume that both critically short telomeres as well as pathogenic variants of TP53 influence jumping translocation formation.

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Section: Discussionmentioning

confidence: 99%

Jumping translocations: Short telomeres or pathogenic TP53 variants as underlying mechanism in acute myeloid leukemia and myelodysplastic syndrome?

Behrens

Thomay

Hagedorn

et al. 2019

Genes Chromosomes & Cancer

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“…In the human genome, short ITSs have been correlated with jumping translocations, a rare case of cytological aberrations in which a fragment of donor chromosome is translocated onto more than one recipient chromosome. This kind of nonreciprocal translocation is frequent in Prader-Willi syndrome and hematological malignancies (Miller et al, 2015;Rivera et al, 1990;Vermeesch et al, 1997). Previous work also reported several kinds of chromosome rearrangements favored by internal telomeric sequences in yeast (Aksenova et al, 2013).…”

Section: Telomeric Identity and Dna Repair Outcomementioning

confidence: 82%

Asymmetric Processing of DNA Ends at a Double-Strand Break Leads to Unconstrained Dynamics and Ectopic Translocation

Marcomini¹,

Shimada²,

Delgoshaie³

et al. 2018

Cell Reports

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Multiple pathways regulate the repair of double-strand breaks (DSBs) to suppress potentially dangerous ectopic recombination. Both sequence and chromatin context are thought to influence pathway choice between non-homologous end-joining (NHEJ) and homology-driven recombination. To test the effect of repetitive sequences on break processing, we have inserted TG-rich repeats on one side of an inducible DSB at the budding yeast MAT locus on chromosome III. Five clustered Rap1 sites within a break-proximal TG repeat are sufficient to block Mre11-Rad50-Xrs2 recruitment, impair resection, and favor elongation by telomerase. The two sides of the break lose end-to-end tethering and show enhanced, uncoordinated movement. Only the TG-free side is resected and shifts to the nuclear periphery. In contrast to persistent DSBs without TG repeats that are repaired by imprecise NHEJ, nearly all survivors of repeat-proximal DSBs repair the break by a homology-driven, non-reciprocal translocation from ChrIII-R to ChrVII-L. This suppression of imprecise NHEJ at TG-repeat-flanked DSBs requires the Uls1 translocase activity.

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“…GCRs assume a variety of forms including deletions, fusions, translocations, allelic recombinants and chromosome loss as well as unstable chromosomes with often unknown structures. Unstable chromosomes are particularly intriguing as they may cause cycles of instability and have been identified as a common intermediate in studies of both Saccharomyces cerevisiae (Admire et al, 2006; Cobb et al, 2005; Myung & Kolodner, 2000; Vasan et al, 2014) and mammalian cells (Breger et al, 2005; Hill & Golic, 2015; Miller et al, 2015). The transient nature of unstable chromosomes can cause different growth rates in the progeny of the cell which originally contained unstable chromosome(s) due to different levels of DNA repair, types of DNA repair, amount gene loss etc., necessitating the development of systems for quantitative and systematic analysis.…”

Section: Introductionmentioning

confidence: 99%

Comparison of Two Budding Yeast Disome Model Systems: Similarities, Difference, and Conflict

Vinton

Langston

2022

Preprint

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Here we define chromosome instability as the propensity of error-prone DNA repair and maintenance to generate chromosomal alterations known as gross chromosomal rearrangements (GCR), which can be found in a variety of forms in a variety of diseased cells. Insights and study of GCRs and chromosome instability can be gained through experimentation using a disome system (a haploid strain with an extra copy of one chromosome). Chromosome instability has previously been investigated and identified in a budding yeast ChrVII disome model. Here we extend and compare the study of chromosome instability using a similar ChrV disome system. As with the ChrVII disome system, cells containing unstable chromosomes form a distinctive sectored colony phenotype and through the use of genetic markers, we also find evidence of allelic recombination and chromosome loss. We also found the same DNA integrity pathways suppress chromosome instability and that unstable chromosomes are not generated through homologous recombination (HR) or non-homologous end-joining (NHEJ), similar to the ChrVII system. But in contrast and more interestingly, we did not detect any altered ChrV sizes, which conflicts with a previous ChrVII disome study where it was thought that unstable chromosomes often resulted in altered sizes. We also discovered a distinct increase in frequency of instability in the ChrV system compared to the ChrVII system.

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Jumping translocations, a novel finding in chronic lymphocytic leukaemia

Cited by 9 publications

References 38 publications

Jumping translocations: Short telomeres or pathogenic TP53 variants as underlying mechanism in acute myeloid leukemia and myelodysplastic syndrome?

Jumping translocations: Short telomeres or pathogenic TP53 variants as underlying mechanism in acute myeloid leukemia and myelodysplastic syndrome?

Asymmetric Processing of DNA Ends at a Double-Strand Break Leads to Unconstrained Dynamics and Ectopic Translocation

Comparison of Two Budding Yeast Disome Model Systems: Similarities, Difference, and Conflict

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