Adipocytes disrupt the translational programme of Acute Lymphoblastic Leukaemia to favour tumour survival and persistence
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ABSTRACT:
PROVIDER: PRJNA637296 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Adipocytes disrupt the translational programme of Acute Lymphoblastic Leukaemia to favour tumour survival and persistence [BM-MSC]
| PRJNA637302 | ENA
Project description:Adipocytes disrupt the translational programme of Acute Lymphoblastic Leukaemia to favour tumour survival and persistence [Nalm-6]
| PRJNA633808 | ENA
Project description: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.
2021-05-25 | GSE151801 | GEO
Project description: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.
2021-05-25 | GSE150832 | GEO
Project description: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.
| S-EPMC8448863 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-05-25 | GSE151802 | GEO
Project description:Nalm-6 cells co-cultured with 3T3-L1 adipocytes or pre-adipocytes were subjected to quantitative LC-MS/MS phosphoproteomic analysis at two timepoints (+24h and +72h) to determine dynamics of cell signalling. Two independent biological replicates were analysed per condition.
2021-06-09 | PXD019186 | Pride
Project description:Post-transcriptional mechanisms are fundamental safeguards of progenitor cell identity and are often dysregulated in cancer. Here, we identified regulators of P-bodies as crucial vulnerabilities in acute myeloid leukaemia (AML) through genome-wide CRISPR screens in normal and malignant haematopoietic progenitors. We found that leukaemia cells harbour aberrantly elevated numbers of P-bodies and show that P-body assembly is crucial for initiation and maintenance of AML. Notably, P-body loss had little effect upon homoeostatic haematopoiesis but impacted regenerative haematopoiesis. Molecular characterization of P-bodies purified from human AML cells unveiled their critical role in sequestering messenger RNAs encoding potent tumour suppressors from the translational machinery. P-body dissolution promoted translation of these mRNAs, which in turn rewired gene expression and chromatin architecture in leukaemia cells. Collectively, our findings highlight the contrasting and unique roles of RNA sequestration in P-bodies during tissue homoeostasis and oncogenesis. These insights open potential avenues for understanding myeloid leukaemia and potential therapeutic interventions.
2024-08-08 | GSE260919 | GEO
Project description:Post-transcriptional mechanisms are fundamental safeguards of progenitor cell identity and are often dysregulated in cancer. Here, we identified regulators of P-bodies as crucial vulnerabilities in acute myeloid leukaemia (AML) through genome-wide CRISPR screens in normal and malignant haematopoietic progenitors. We found that leukaemia cells harbour aberrantly elevated numbers of P-bodies and show that P-body assembly is crucial for initiation and maintenance of AML. Notably, P-body loss had little effect upon homoeostatic haematopoiesis but impacted regenerative haematopoiesis. Molecular characterization of P-bodies purified from human AML cells unveiled their critical role in sequestering messenger RNAs encoding potent tumour suppressors from the translational machinery. P-body dissolution promoted translation of these mRNAs, which in turn rewired gene expression and chromatin architecture in leukaemia cells. Collectively, our findings highlight the contrasting and unique roles of RNA sequestration in P-bodies during tissue homoeostasis and oncogenesis. These insights open potential avenues for understanding myeloid leukaemia and potential therapeutic interventions.
2024-08-08 | GSE224643 | GEO
Project description:Acute Myeloid Leukaemia (AML) carries a 5 year survival rate of just 24%. Toxic chemotherapy regimens remain the backbone of standard of care for AML. The FLT3 tyrosine kinase is a recognised AML oncogene, with FLT3 activating mutations occurring in approximately one third of all AML patients. However, therapeutic targeting of FLT3 has proven difficult as monotherapy, with the development of drug resistance and relapse. Characterisation of the signalling pathways regulated by mutant FLT3 is required to identify better therapeutic strategies.
2019-12-20 | MSV000084730 | MassIVE