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Adipocytes disrupt the translational programme of Acute Lymphoblastic Leukaemia to favour tumour survival and persistence

ABSTRACT: Adipocytes disrupt the translational programme of Acute Lymphoblastic Leukaemia to favour tumour survival and persistence

PROVIDER: PRJNA637296 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11811420_1.fastq.gz	Fastqsanger.gz
	SRR11811420_2.fastq.gz	Fastqsanger.gz
	SRR11811421_1.fastq.gz	Fastqsanger.gz
	SRR11811421_2.fastq.gz	Fastqsanger.gz
	SRR11811422_1.fastq.gz	Fastqsanger.gz

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Adipocytes disrupt the translational programme of Acute Lymphoblastic Leukaemia to favour tumour survival and persistence [Nalm-6]

Project description:Adipocytes disrupt the translational programme of Acute Lymphoblastic Leukaemia to favour tumour survival and persistence [Nalm-6]

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Adipocytes disrupt the translational programme of Acute Lymphoblastic Leukaemia to favour tumour survival and persistence [BM-MSC]

Project description:Adipocytes disrupt the translational programme of Acute Lymphoblastic Leukaemia to favour tumour survival and persistence [BM-MSC]

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Adipocytes disrupt the translational programme of Acute Lymphoblastic Leukaemia to favour tumour survival and persistence [Nalm-6]

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.

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Adipocytes disrupt the translational programme of Acute Lymphoblastic Leukaemia to favour tumour survival and persistence [BM-MSC]

2021-05-25 | GSE151801 | GEO

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

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.

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Adipocytes disrupt the translational programme of Acute Lymphoblastic Leukaemia to favour tumour survival and persistence

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2021-05-25 | GSE151802 | GEO

Adipocytes disrupt the translational programme of Acute Lymphoblastic Leukaemia to favour tumour survival and persistence

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.

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