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Spatial chromosome folding and active transcription drive DNA fragility and formation of oncogenic MLL translocations

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE121742 | GEO | 2019/06/12

REPOSITORIES: GEO

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Spatial chromosome folding and active transcription drive DNA fragility and formation of oncogenic MLL translocations [RNA-Seq]

Project description:How spatial chromosome organization influences genome integrity is still poorly understood. Here we show that DNA double-strand breaks (DSBs) mediated by topoisomerase 2 (TOP2) activities, are enriched at chromatin loop anchors with high transcriptional activity. Recurrent DSBs occur at CTCF/cohesin bound sites at the bases of chromatin loops and their frequency positively correlates with transcriptional output and directionality. The physiological relevance of this preferential positioning is indicated by the finding that genes recurrently translocating to drive leukemias, are highly transcribed and are enriched at loop anchors. These genes accumulate DSBs at recurrent hot spots that give rise to chromosomal fusions relying on the activity of both TOP2 isoforms and on transcriptional elongation. We propose that transcription and 3D chromosome folding jointly pose a threat to genomic stability, and are key contributors to the occurrence of genome rearrangements that drive cancer.

2019-06-12 | GSE121741 | GEO

Spatial chromosome folding and active transcription drive DNA fragility and formation of oncogenic MLL translocations [BLISS-Seq]

2019-06-12 | GSE121740 | GEO

Spatial chromosome folding and active transcription drive DNA fragility and formation of oncogenic MLL translocations

Project description:Spatial chromosome folding and active transcription drive DNA fragility and formation of oncogenic MLL translocations

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Spatial chromosome folding and active transcription drive DNA fragility and formation of oncogenic MLL translocations [RNA-Seq]

Project description:Spatial chromosome folding and active transcription drive DNA fragility and formation of oncogenic MLL translocations [RNA-Seq]

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Spatial chromosome folding and active transcription drive DNA fragility and formation of oncogenic MLL translocations [BLISS-Seq]

Project description:Spatial chromosome folding and active transcription drive DNA fragility and formation of oncogenic MLL translocations [BLISS-Seq]

| PRJNA498296 | ENA

Spatial dynamics of chromosome translocations in living cells.

Project description:Chromosome translocations are a hallmark of cancer cells. We have developed an experimental system to visualize the formation of translocations in living cells and apply it to characterize the spatial and dynamic properties of translocation formation. We demonstrate that translocations form within hours of the occurrence of double-strand breaks (DSBs) and that their formation is cell cycle-independent. Translocations form preferentially between prepositioned genome elements, and perturbation of key factors of the DNA repair machinery uncouples DSB pairing from translocation formation. These observations generate a spatiotemporal framework for the formation of translocations in living cells.

| S-EPMC6324928 | biostudies-literature

Chromosomal translocations involving the MLL gene: molecular mechanisms.

Project description:A wide array of recurrent, non-random chromosomal translocations are associated with hematologic malignancies; experimental models have clearly demonstrated that many of these translocations are causal events during malignant transformation. Translocations involving the MLL gene are among the most common of these non-random translocations. Leukemias with MLL translocations have been the topic of intense interest because of the unusual, biphenotypic immunophenotype of these leukemias, because of the unique clinical presentation of some MLL translocations (infant leukemia and therapy-related leukemia), and because of the large number of different chromosomal loci that partner with MLL in these translocations. This review is focused on the potential mechanisms that lead to MLL translocations, and will discuss aberrant VDJ recombination, Alu-mediated recombination, non-homologous end joining, as well as the effect of DNA topoisomerase II poisons and chromatin structure.

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Genome Organization Drives Chromosome Fragility.

Project description:In this study, we show that evolutionarily conserved chromosome loop anchors bound by CCCTC-binding factor (CTCF) and cohesin are vulnerable to DNA double strand breaks (DSBs) mediated by topoisomerase 2B (TOP2B). Polymorphisms in the genome that redistribute CTCF/cohesin occupancy rewire DNA cleavage sites to novel loop anchors. While transcription- and replication-coupled genomic rearrangements have been well documented, we demonstrate that DSBs formed at loop anchors are largely transcription-, replication-, and cell-type-independent. DSBs are continuously formed throughout interphase, are enriched on both sides of strong topological domain borders, and frequently occur at breakpoint clusters commonly translocated in cancer. Thus, loop anchors serve as fragile sites that generate DSBs and chromosomal rearrangements. VIDEO ABSTRACT.

| S-EPMC6133249 | biostudies-literature

Circular RNAs drive oncogenic chromosomal translocations through R-loop-mediated genome instability

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-05-01 | GSE125986 | GEO

Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia.

Project description:Translocations involving the mixed lineage leukemia (MLL) gene result in human acute leukemias with very poor prognosis. The leukemogenic activity of MLL fusion proteins is critically dependent on their direct interaction with menin, a product of the multiple endocrine neoplasia (MEN1) gene. Here we present what are to our knowledge the first small-molecule inhibitors of the menin-MLL fusion protein interaction that specifically bind menin with nanomolar affinities. These compounds effectively reverse MLL fusion protein-mediated leukemic transformation by downregulating the expression of target genes required for MLL fusion protein oncogenic activity. They also selectively block proliferation and induce both apoptosis and differentiation of leukemia cells harboring MLL translocations. Identification of these compounds provides a new tool for better understanding MLL-mediated leukemogenesis and represents a new approach for studying the role of menin as an oncogenic cofactor of MLL fusion proteins. Our findings also highlight a new therapeutic strategy for aggressive leukemias with MLL rearrangements.

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