Centre for Haemato-Oncology, Barts Cancer Institute, John Vane Science Centre, Charterhouse Square, Queen Mary University of London, London, UK.
BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, Scotland, UK.
Nat Commun. 2021 Sep 17;12(1):5507. doi: 10.1038/s41467-021-25540-4.
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.
在诱导化疗后促进原发性疾病和急性淋巴细胞白血病（ALL）存活的特定小生境适应性仍不清楚。在这里，我们表明骨髓（BM）脂肪细胞在 ALL 发病机制和治疗过程中动态演变，从原发性白血病小生境中的细胞耗竭转变为缓解诱导后完全重建状态。功能上，脂肪细胞小生境促使 ALL 细胞向缓慢增殖和细胞静止的命运转变，突出了脂肪细胞动态对疾病建立和化疗耐药性的关键贡献。从机制上讲，脂肪细胞小生境相互作用靶向转录后网络，并抑制 ALL 细胞中的蛋白质生物合成。用一般控制不可诱导 2 抑制剂（GCN2ib）治疗可减轻脂肪细胞介导的翻译抑制作用，并挽救 ALL 细胞静止，从而显著降低脂肪细胞对化疗和其他外在应激源的细胞保护作用。这些数据确立了脂肪细胞驱动的 ALL 蛋白质组限制如何有利于 ALL 肿瘤，防止其消除，并为操纵脂肪细胞介导的 ALL 耐药性提供了思路。
