• Login
    View Item 
    •   Home
    • The Manchester Institute Cancer Research UK
    • All Paterson Institute for Cancer Research
    • View Item
    •   Home
    • The Manchester Institute Cancer Research UK
    • All Paterson Institute for Cancer Research
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of ChristieCommunitiesTitleAuthorsIssue DateSubmit DateSubjectsThis CollectionTitleAuthorsIssue DateSubmit DateSubjects

    My Account

    LoginRegister

    Local Links

    The Christie WebsiteChristie Library and Knowledge Service

    Statistics

    Display statistics

    Blast cells surviving acute myeloid leukemia induction therapy are in cycle with a signature of FOXM1 activity

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Thumbnail
    Name:
    34711181.pdf
    Size:
    1.894Mb
    Format:
    PDF
    Description:
    From UNPAYWALL
    Download
    Authors
    Williams, Mark S
    Basma, Naseer J
    Amaral, Fabio
    Wiseman, Daniel H
    Somervaille, Tim C P
    Affiliation
    Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, Oglesby Cancer Research Building, The University of Manchester, 555 Wilmslow Road, Manchester, M20 4GJ, UK
    Issue Date
    2021
    
    Metadata
    Show full item record
    Abstract
    Background: Disease relapse remains common following treatment of acute myeloid leukemia (AML) and is due to chemoresistance of leukemia cells with disease repopulating potential. To date, attempts to define the characteristics of in vivo resistant blasts have focused on comparisons between leukemic cells at presentation and relapse. However, further treatment responses are often seen following relapse, suggesting that most blasts remain chemosensitive. We sought to characterise in vivo chemoresistant blasts by studying the transcriptional and genetic features of blasts from before and shortly after induction chemotherapy using paired samples from six patients with primary refractory AML. Methods: Leukemic blasts were isolated by fluorescence-activated cell sorting. Fluorescence in situ hybridization (FISH), targeted genetic sequencing and detailed immunophenotypic analysis were used to confirm that sorted cells were leukemic. Sorted blasts were subjected to RNA sequencing. Lentiviral vectors expressing short hairpin RNAs were used to assess the effect of FOXM1 knockdown on colony forming capacity, proliferative capacity and apoptosis in cell lines, primary AML cells and CD34+ cells from healthy donors. Results: Molecular genetic analysis revealed early clonal selection occurring after induction chemotherapy. Immunophenotypic characterisation found leukemia-associated immunophenotypes in all cases that persisted following treatment. Despite the genetic heterogeneity of the leukemias studied, transcriptional analysis found concerted changes in gene expression in resistant blasts. Remarkably, the gene expression signature suggested that post-chemotherapy blasts were more proliferative than those at presentation. Resistant blasts also appeared less differentiated and expressed leukemia stem cell (LSC) maintenance genes. However, the proportion of immunophenotypically defined LSCs appeared to decrease following treatment, with implications for the targeting of these cells on the basis of cell surface antigen expression. The refractory gene signature was highly enriched with targets of the transcription factor FOXM1. shRNA knockdown experiments demonstrated that the viability of primary AML cells, but not normal CD34+ cells, depended on FOXM1 expression. Conclusions: We found that chemorefractory blasts from leukemias with varied genetic backgrounds expressed a common transcriptional program. In contrast to the notion that LSC quiescence confers resistance to chemotherapy we find that refractory blasts are both actively proliferating and enriched with LSC maintenance genes. Using primary patient material from a relevant clinical context we also provide further support for the role of FOXM1 in chemotherapy resistance, proliferation and stem cell function in AML.
    Citation
    Williams MS, Basma NJ, Amaral FMR, Wiseman DH, Somervaille TCP. Blast cells surviving acute myeloid leukemia induction therapy are in cycle with a signature of FOXM1 activity [Internet]. Vol. 21, BMC Cancer. Springer Science and Business Media LLC; 2021.
    Journal
    BMC Cancer
    URI
    http://hdl.handle.net/10541/624793
    DOI
    10.1186/s12885-021-08839-9
    PubMed ID
    34711181
    Additional Links
    https://dx.doi.org/10.1186/s12885-021-08839-9
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1186/s12885-021-08839-9
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

    entitlement

    Related articles

    • High GPR56 surface expression correlates with a leukemic stem cell gene signature in CD34-positive AML.
    • Authors: Daga S, Rosenberger A, Quehenberger F, Krisper N, Prietl B, Reinisch A, Zebisch A, Sill H, Wölfler A
    • Issue date: 2019 Apr
    • Determination of P-glycoprotein, MDR-related protein 1, breast cancer resistance protein, and lung-resistance protein expression in leukemic stem cells of acute myeloid leukemia.
    • Authors: de Figueiredo-Pontes LL, Pintão MC, Oliveira LC, Dalmazzo LF, Jácomo RH, Garcia AB, Falcão RP, Rego EM
    • Issue date: 2008 May
    • FOXM1 regulates leukemia stem cell quiescence and survival in MLL-rearranged AML.
    • Authors: Sheng Y, Yu C, Liu Y, Hu C, Ma R, Lu X, Ji P, Chen J, Mizukawa B, Huang Y, Licht JD, Qian Z
    • Issue date: 2020 Feb 17
    • FOXM1 contributes to treatment failure in acute myeloid leukemia.
    • Authors: Khan I, Halasi M, Patel A, Schultz R, Kalakota N, Chen YH, Aardsma N, Liu L, Crispino JD, Mahmud N, Frankfurt O, Gartel AL
    • Issue date: 2018 Aug 9
    • 5-aminoimidazole-4-carboxamide ribonucleoside induces differentiation in a subset of primary acute myeloid leukemia blasts.
    • Authors: Dembitz V, Lalic H, Kodvanj I, Tomic B, Batinic J, Dubravcic K, Batinic D, Bedalov A, Visnjic D
    • Issue date: 2020 Nov 11
    DSpace software (copyright © 2002 - 2023)  DuraSpace
    Quick Guide | Contact Us
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.