BioProject

Reprogramming of bone marrow microenvironments (BMMs) is a key process by which ALL cells gain resilience however the specific adaptations that facilitate primary disease and ALL survival after induction chemotherapy remain unclear. More...

Reprogramming of bone marrow microenvironments (BMMs) is a key process by which ALL cells gain resilience however the specific adaptations that facilitate primary disease and ALL survival after induction chemotherapy remain unclear. Using temporal analysis of clinical biopsies we identify that BM adipocytes are profoundly remodelled during ALL pathogenesis and treatment transitioning from cellular depletion within the primary leukaemia niche to a fully restored state upon remission treatment highlighting the specific and selective participation of adipocyte stroma in the chemotherapy context.  The functional relevance of these dynamics was revealed through modelling studies demonstrating that adipocytes non- cell autonomously regulate ALL development by reducing proliferative capacity whilst simultaneously increasing leukaemia cell quiescence. Thus, adipocyte dynamics mark a transition in the functional organisation of BMM from one that favours emergent ALL to an adverse setting for chemotherapeutic effects. Mechanistically, we show that adipocyte induced tumour suppression, accompanies rapid but reversible non canonical translational arrest revealing a novel regulatory relationship that executes at the level of the leukaemia proteome to lower ALL expansion. Importantly, adipocyte remodelled ALL proteomes adopt a distinct, reversible, stress-resistant state which was independent of cell cycle status underscoring the importance of therapy emergent adipocyte niches in conferring global tumour cell protection. These studies reveal the critical contribution of adipocyte mediated repression of the ALL proteome as another mode of microenviromental intervention advantaging ALL tumours to prevent their elimination.  Overall design: RNA-seq experiment with n=3 biological replicates of Nalm-6 co-cultured with 3T3-L1 Pre-adipocytes or 3T3-L1 Adipocytes as described Less...