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

Q. Heydt, C. Xintaropoulou, A. Clear, M. Austin, I. Pislariu, F. Miraki-Moud, P. Cutillas, K. Korfi, M. Calaminici, W. Cawthorn, K. Suchacki, A. Nagano, J. G. Gribben, M. Smith, J. D. Cavenagh, H. Oakervee, A. Castleton, D. Taussig, B. Peck, A. Wilczynska, L. McNaughton, D. Bonnet, F. Mardakheh and B. Patel ()
Additional contact information
Q. Heydt: Queen Mary University of London
C. Xintaropoulou: Queen Mary University of London
A. Clear: Queen Mary University of London
M. Austin: Queen Mary University of London
I. Pislariu: Queen Mary University of London
F. Miraki-Moud: Queen Mary University of London
P. Cutillas: Queen Mary University of London
K. Korfi: Queen Mary University of London
M. Calaminici: Queen Mary University of London
W. Cawthorn: University of Edinburgh
K. Suchacki: University of Edinburgh
A. Nagano: Queen Mary University of London
J. G. Gribben: Queen Mary University of London
M. Smith: St Bartholomew’s Hospital, West Smithfield
J. D. Cavenagh: St Bartholomew’s Hospital, West Smithfield
H. Oakervee: St Bartholomew’s Hospital, West Smithfield
A. Castleton: Christie NHS Foundation Trust
D. Taussig: The Royal Marsden Hospital
B. Peck: Queen Mary University of London
A. Wilczynska: CRUK Beatson Institute
L. McNaughton: The Francis Crick Institute
D. Bonnet: The Francis Crick Institute
F. Mardakheh: Queen Mary University of London
B. Patel: Queen Mary University of London

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25540-4

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