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DNA fragility at the KMT2A/MLL locus: insights from old and new technologies

Lookup NU author(s): Dr Ian CowellORCiD, Professor Caroline AustinORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

The Mixed-Lineage Leukaemia (MLL/KMT2A) gene is frequently rearranged in childhood and adult acute leukaemia (AL) and in secondary leukaemias occurring after therapy with DNA topoisomerase targeting anti-cancer agents such as etoposide (t-AL). MLL/KMT2A chromosome translocation break sites in AL patients fall within an 8 kb breakpoint cluster region (BCR). Furthermore, MLL/KMT2A break sites in t-AL frequently occur in a much smaller region, or hotspot, towards the 3' end of the BCR, close to the intron 11/exon 12 boundary. These findings have prompted considerable effort to uncover mechanisms behind the apparent fragility of the BCR and particularly the t-AL hotspot. Recent genome-wide analyses have demonstrated etoposide-induced DNA cleavage within the BCR, and it is tempting to conclude that this cleavage explains the distribution of translocation break sites in t-AL. However, the t-AL hotspot and the centre of the observed preferential DNA cleavage are offset by over 250 nucleotides, suggesting additional factors contribute to the distribution of t-AL break sites. We review these recent genomic datasets along with older experimental results, analysis of TOP2 DNA cleavage site preferences and DNA secondary structure features that may lead to break site selection in t-AL MLL/KMT2A translocations.


Publication metadata

Author(s): Cowell IG, Austin CA

Publication type: Review

Publication status: Published

Journal: Open Biology

Year: 2023

Volume: 13

Issue: 1

Online publication date: 11/01/2023

Acceptance date: 22/11/2022

ISSN (electronic): 2046-2441

Publisher: Royal Society Publishing

URL: https://doi.org/10.1098/rsob.220232

DOI: 10.1098/rsob.220232

PubMed id: 36629017


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