Adipocytes disrupt the translational programme of acute lymphoblastic leukaemia to favour tumour survival and persistence.
Adipocytes disrupt the translational programme of acute lymphoblastic leukaemia to favour tumour survival and persistence.
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DOI：
10.1038/s41467-021-25540-4
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发表时间：
2021-09-17
影响因子：
16.6
通讯作者：
Patel B
中科院分区：
文献类型：
--
作者：
Heydt Q;Xintaropoulou C;Clear A;Austin M;Pislariu I;Miraki-Moud F;Cutillas P;Korfi K;Calaminici M;Cawthorn W;Suchacki K;Nagano A;Gribben JG;Smith M;Cavenagh JD;Oakervee H;Castleton A;Taussig D;Peck B;Wilczynska A;McNaughton L;Bonnet D;Mardakheh F;Patel B
诱导化疗后促进原发疾病和急性淋巴细胞白血病(ALL)存活的特定生态位适应尚不清楚。在这里，我们展示了骨髓脂肪细胞在所有发病机制和治疗过程中的动态演变，从原发白血病小生境中的细胞枯竭过渡到缓解诱导后的完全重建状态。在功能上，脂肪细胞的生态位引起所有细胞的命运转换，转向缓慢增殖和细胞静止，突出了脂肪细胞动态对疾病建立和化疗耐药的关键贡献。从机制上讲，脂肪细胞的小生境相互作用针对转录后网络，并抑制所有细胞中的蛋白质生物合成。一般对照的不可降压2抑制剂(GCN2ib)可减轻脂肪细胞介导的翻译抑制，挽救所有细胞静止，从而显着降低脂肪细胞对化疗和其他外在应激源的细胞保护作用。这些数据确定了脂肪细胞驱动的限制所有蛋白质组如何使所有肿瘤受益，防止它们被消除，并提出了操纵脂肪细胞介导的所有耐药的方法。在诱导化疗期间，骨髓微环境如何演变以促进急性淋巴细胞白血病(ALL)的生存仍不清楚。在这里，作者表明，在所有治疗中出现的脂肪细胞通过对ALL蛋白质组的限制作用来帮助所有细胞存活。
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.
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影响因子：
11.2
作者：
Ehsanipour EA;Sheng X;Behan JW;Wang X;Butturini A;Avramis VI;Mittelman SD
通讯作者：
Mittelman SD
影响因子：
64.5
作者：
Baryawno, Ninib;Przybylski, Dariusz;Scadden, David T.
通讯作者：
Scadden, David T.
影响因子：
20.3
作者：
Brüggemann, M;Raff, T;Kneba, M
通讯作者：
Kneba, M
影响因子：
7.5
作者：
Cahu, Xavier;Calvo, Julien;Pflumio, Francoise
通讯作者：
Pflumio, Francoise
白血病增殖细胞根据治疗重建不断进化的生态位
影响因子：
50.3
作者：
Duan, Cai-Wen;Shi, Jun;Hong, Deng-Li
通讯作者：
Hong, Deng-Li