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    Targeted nanopore sequencing for the identification of ABCB1 promoter translocations in cancer

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    Authors
    Williams, Mark S
    Basma, Naseer J
    Amaral, Fabio
    Williams, Gillian
    Weightman, John
    Breitwieser, Wolfgang
    Nelson, Louisa
    Taylor, Stephen S
    Wiseman, Daniel H
    Somervaille, Tim C P
    Affiliation
    Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, Oglesby Cancer Research Building, The University of Manchester, Manchester, M20 4GJ, UK.
    Issue Date
    2020
    
    Metadata
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    Abstract
    Background: Resistance to chemotherapy is the most common cause of treatment failure in acute myeloid leukemia (AML) and the drug efflux pump ABCB1 is a critical mediator. Recent studies have identified promoter translocations as common drivers of high ABCB1 expression in recurrent, chemotherapy-treated high-grade serous ovarian cancer (HGSC) and breast cancer. These fusions place ABCB1 under the control of a strong promoter while leaving its open reading frame intact. The mechanisms controlling high ABCB1 expression in AML are largely unknown. We therefore established an experimental system and analysis pipeline to determine whether promoter translocations account for high ABCB1 expression in cases of relapsed human AML. Methods: The human AML cell line THP-1 was used to create a model of chemotherapy resistance in which ABCB1 expression was driven by a promoter fusion. The THP-1 model was used to establish a targeted nanopore long-read sequencing approach that was then applied to cases of ABCB1high HGSC and AML. H3K27Ac ChIP sequencing was used to assess the activity of native promoters in cases of ABCB1high AML. Results: Prolonged in vitro daunorubicin exposure induced activating ABCB1 promoter translocations in human THP-1 AML cells, similar to those recently described in recurrent high-grade serous ovarian and breast cancers. Targeted nanopore sequencing proved an efficient method for identifying ABCB1 structural variants in THP-1 AML cells and HGSC; the promoter translocations identified in HGSC were both previously described and novel. In contrast, activating ABCB1 promoter translocations were not identified in ABCB1high AML; instead H3K27Ac ChIP sequencing demonstrated active native promoters in all cases studied. Conclusions: Despite frequent high level expression of ABCB1 in relapsed primary AML we found no evidence of ABCB1 translocations and instead confirmed high-level activity of native ABCB1 promoters, consistent with endogenous regulation. Keywords: ABCB1; Acute myeloid leukemia; Drug resistance; HGSC; Ovarian cancer; Promoter translocation.
    Citation
    Williams MS, Basma NJ, Amaral FMR, Williams G, Weightman JP, Breitwieser W, et al. Targeted nanopore sequencing for the identification of ABCB1 promoter translocations in cancer. BMC Cancer. 2020;20(1):1075.
    Journal
    BMC Cancer
    URI
    http://hdl.handle.net/10541/623514
    DOI
    10.1186/s12885-020-07571-0
    PubMed ID
    33167906
    Additional Links
    https://dx.doi.org/10.1186/s12885-020-07571-0
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1186/s12885-020-07571-0
    Scopus Count
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    All Paterson Institute for Cancer Research

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