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    Adipocytes disrupt the translational programme of acute lymphoblastic leukaemia to favour tumour survival and persistence

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    Authors
    Heydt, Q.
    Xintaropoulou, C.
    Clear, A.
    Austin, M.
    Pislariu, I.
    Miraki-Moud, F.
    Cutillas, P.
    Korfi, K.
    Calaminici, M.
    Cawthorn, W.
    Suchacki, K.
    Nagano, A.
    Gribben, J. G.
    Smith, M.
    Cavenagh, J. D.
    Oakervee, H.
    Castleton, Anna
    Taussig, D.
    Peck, B.
    Wilczynska, A.
    McNaughton, L.
    Bonnet, D.
    Mardakheh, F.
    Patel, B.
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    Affiliation
    Centre for Haemato-Oncology, Barts Cancer Institute, John Vane Science Centre, Charterhouse Square, Queen Mary University of London, London, UK
    Issue Date
    2021
    
    Metadata
    Show full item record
    Abstract
    The specific niche adaptations that facilitate primary disease and Acute Lymphoblastic Leukaemia (ALL) survival after induction chemotherapy remain unclear. Here, we show that Bone Marrow (BM) adipocytes dynamically evolve during ALL pathogenesis and therapy, transitioning from cellular depletion in the primary leukaemia niche to a fully reconstituted state upon remission induction. Functionally, adipocyte niches elicit a fate switch in ALL cells towards slow-proliferation and cellular quiescence, highlighting the critical contribution of the adipocyte dynamic to disease establishment and chemotherapy resistance. Mechanistically, adipocyte niche interaction targets posttranscriptional networks and suppresses protein biosynthesis in ALL cells. Treatment with general control nonderepressible 2 inhibitor (GCN2ib) alleviates adipocyte-mediated translational repression and rescues ALL cell quiescence thereby significantly reducing the cytoprotective effect of adipocytes against chemotherapy and other extrinsic stressors. These data establish how adipocyte driven restrictions of the ALL proteome benefit ALL tumours, preventing their elimination, and suggest ways to manipulate adipocyte-mediated ALL resistance.
    Citation
    Heydt Q, Xintaropoulou C, Clear A, Austin M, Pislariu I, Miraki-Moud F, et al. Adipocytes disrupt the translational programme of acute lymphoblastic leukaemia to favour tumour survival and persistence. Nat Commun. 2021 Sep 17;12(1).
    Journal
    Nature Communications
    URI
    http://hdl.handle.net/10541/624609
    DOI
    10.1038/s41467-021-25540-4
    PubMed ID
    34535653
    Additional Links
    https://dx.doi.org/10.1038/s41467-021-25540-4
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41467-021-25540-4
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