Adipocytes disrupt the translational programme of acute lymphoblastic leukaemia to favour tumour survival and persistence
The particular niche adaptations that facilitate primary disease and Acute Lymphoblastic Leukaemia (ALL) survival after induction chemotherapy remain unclear. Here, we reveal that Bone Marrow (BM) adipocytes dynamically evolve during ALL pathogenesis and therapy, transitioning from cellular depletion however leukaemia niche to some fully reconstituted condition upon remission induction. Functionally, adipocyte niches elicit a fate switch in most cells towards slow-proliferation and cellular quiescence, highlighting the critical contribution from the adipocyte dynamic to disease establishment and chemotherapy resistance. Mechanistically, adipocyte niche interaction targets posttranscriptional systems and suppresses protein biosynthesis in most cells. Treatment with general control nonderepressible 2 inhibitor (GCN2ib) alleviates adipocyte-mediated translational repression and rescues ALL cell quiescence therefore considerably lowering the cytoprotective aftereffect of adipocytes against chemotherapy along with other extrinsic stressors. These data establish how adipocyte driven limitations from the ALL proteome benefit ALL tumours, stopping their elimination, and suggest methods to manipulate adipocyte-mediated ALL resistance.