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

Heydt, Q. et al. (2021) Adipocytes disrupt the translational programme of acute lymphoblastic leukaemia to favour tumour survival and persistence. Nature Communications, 12, 5507. (doi: 10.1038/s41467-021-25540-4) (PMID:34535653) (PMCID:PMC8448863)

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.

• Item Type: Articles
• Additional Information: This work was supported by Blood Cancer UK (grant 15009; B Patel), The Greg Wolf Foundation (B Patel) Cancer Research UK (grant CRUK A21019; B Patel, co-applicant), and Gabrielle’s Angels Foundation (B Patel). W.C. was supported by a grant from the Medical Research Council (MR/M021394/1). This work was supported by a Cancer Research UK Centre Grant C16420/A18066.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Wilczynska, Dr Ania
• 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, A., Taussig, D., Peck, B., Wilczynska, A., McNaughton, L., Bonnet, D., Mardakheh, F., and Patel, B.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Nature Communications 12: 5507
• Publisher Policy: Reproduced under a Creative Commons License