1. Adipocytes disrupt the translational programme of acute lymphoblastic leukaemia to favour tumour survival and persistence
- Author
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Andrew Clear, Anna Castleton, James D. Cavenagh, Heather Oakervee, Farideh Miraki-Moud, Pedro R. Cutillas, Bella Patel, Koorosh Korfi, Linda Ariza McNaughton, C. Xintaropoulou, F. Mardakheh, Dominique Bonnet, Ania Wilczynska, I. Pislariu, Ai Nagano, Michael J Austin, Martyn T. Smith, Karla J. Suchacki, John G. Gribben, Mariarita Calaminici, Q. Heydt, David Taussig, B. Peck, and William P. Cawthorn
- Subjects
Adult ,Cancer microenvironment ,Proteome ,Cell Survival ,medicine.medical_treatment ,Biopsy ,Science ,General Physics and Astronomy ,Disease ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Pathogenesis ,chemistry.chemical_compound ,Mice ,Young Adult ,Cell quiescence ,Bone Marrow ,Stress, Physiological ,Adipocyte ,3T3-L1 Cells ,hemic and lymphatic diseases ,medicine ,Adipocytes ,Animals ,Humans ,Cell Lineage ,Chemotherapy ,Human Biology & Physiology ,Multidisciplinary ,Acute lymphocytic leukaemia ,Stem Cells ,Induction chemotherapy ,General Chemistry ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Tumour Biology ,Survival Analysis ,medicine.anatomical_structure ,chemistry ,Cancer research ,Bone marrow - 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., How the bone marrow microenvironment evolves during induction chemotherapy to facilitate acute lymphoblastic leukaemia (ALL) survival remains unclear. Here the authors show that adipocytes emergent during ALL therapy aid the survival of ALL cells through a restrictive effect on the ALL proteome.
- Published
- 2021
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