A systematic description of MLL fusion gene formation

Wright, Randall; Vaughan, Andrew T M

doi:10.1016/j.critrevonc.2014.03.004

Cited by 32 publications

(39 citation statements)

References 68 publications

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“…When TOP2-induced DSBs are not faithfully re-ligated, they are susceptible to mutation and genome rearrangements. Indeed, the widely used anti-cancer agent etoposide (ETO), which traps TOP2 in the double-strand cleavage form and thereby prevents ligation, is frequently associated with therapy-related myeloid leukemias (t-AML) following a primary malignancy (Wright and Vaughan, 2014). …”

Section: Introductionmentioning

confidence: 99%

Genome Organization Drives Chromosome Fragility

Canela

Maman

Jung

et al. 2017

Cell

346

416

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SUMMARY In this study, we show that evolutionarily conserved chromosome loop anchors bound by 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.

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Section: Introductionmentioning

confidence: 99%

Genome Organization Drives Chromosome Fragility

Canela

Maman

Jung

et al. 2017

Cell

346

416

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“…While the major pathological mechanisms underlying most of these mutations are not fully understood, it is clear that mutations and rearrangements of the MLL family proteins are important in the initiation and maintenance of broad range of cancers. The reader who is further interested in the intricacies of MLL disease mechanisms will find the following references particularly enlightening . Extensive implications of SET1 family of proteins in diseases validate these proteins as potential drug targets.…”

Section: Introductionmentioning

confidence: 99%

Targeting human SET1/MLL family of proteins

et al. 2017

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The SET1 family of proteins, and in particular MLL1, are essential regulators of transcription and key mediators of normal development and disease. Here, we summarize the detailed characterization of the methyltransferase activity of SET1 complexes and the role of the key subunits, WDR5, RbBP5, ASH2L, and DPY30. We present new data on full kinetic characterization of human MLL1, MLL3, SET1A, and SET1B trimeric, tetrameric, and pentameric complexes to elaborate on substrate specificities and compare our findings with what has been reported before. We also review exciting recent work identifying potent inhibitors of oncogenic MLL1 function through disruption of protein–protein interactions within the MLL1 complex.

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“…Simultaneous transcription of the mutated DMPK gene and the CTNNB1 gene in cycling hair follicles might be responsible for tissue and gene specificity and could be an explanation for the putative mutation signatures detected in the patient's tumor specimens which suggest a transcriptional mutational bias. In other cancers, co-transcription has been proposed as a mechanism responsible for gene fusions [35]. Simultaneous transcription of DMPK and CTNNB1 resulting in a defect of transcription coupled DNA repair at the CTMNB1 gene could further provide an explanation why no additional mutation could be detected within the other 160 cancer-related genes which were screened by NGS even though the patient obviously displays a hypermutation phenotype.…”

Section: Discussionmentioning

confidence: 99%