美国罗切斯特大学Jeevisha Bajaj小组的一项最新研究提出了来自肿瘤生态位的牛磺酸驱动糖酵解促进白血病的发生。2025年5月14日出版的《自然》发表了这项成果。

该研究团队采用时序单细胞RNA测序（scRNA-seq）来鉴定来自骨髓基质生态位的分子线索，这些分子线索在致癌进展过程中参与白血病干细胞富集细胞（LSCs）。研究组将这些数据与他们的人类LSC RNA-seq和LSC依赖性的体内CRISPR筛选相结合，以确定LSC -利基相互作用对白血病发生至关重要。这些分析确定牛磺酸-牛磺酸转运蛋白（TAUT）轴是侵袭性髓性白血病的关键依赖性。

研究人员发现半胱氨酸双加氧酶1型（CDO1）驱动的牛磺酸生物合成仅限于骨系细胞，并在髓系疾病进展过程中增加。阻断骨脂细胞中CDO1的表达会损害LSC的生长并改善生存结果。通过使用TAUT基因功能缺失模型和患者源性急性髓性白血病（AML）细胞，研究人员发现TAUT抑制显著损害了体内髓性白血病的进展。与venetoclax耐药AML中TAUT表达升高一致，TAUT抑制与venetoclax协同抑制人类AML原代细胞的生长。从机制上讲，他们的多组学方法表明牛磺酸摄取的丧失抑制了RAG-GTP依赖的mTOR激活和下游糖酵解。总的来说，他们的工作建立了白血病进展过程中基质信号的时间格局，并确定牛磺酸是髓系恶性肿瘤的关键调节因子。

据介绍，已知来自微环境的信号对发育、干细胞自我更新和致癌进展至关重要。尽管已经确定了一些促进癌症进展的利基驱动信号，但缺乏对癌症干细胞受体的疾病相关微环境配体的协同努力。

附：英文原文

Title: Taurine from tumour niche drives glycolysis to promote leukaemogenesis

Author: Sharma, Sonali, Rodems, Benjamin J., Baker, Cameron D., Kaszuba, Christina M., Franco, Edgardo I., Smith, Bradley R., Ito, Takashi, Swovick, Kyle, Welle, Kevin, Zhang, Yi, Rock, Philip, Chaves, Francisco A., Ghaemmaghami, Sina, Calvi, Laura M., Ganguly, Archan, Burack, W. Richard, Becker, Michael W., Liesveld, Jane L., Brookes, Paul S., Munger, Joshua C., Jordan, Craig T., Ashton, John M., Bajaj, Jeevisha

Issue&Volume: 2025-05-14

Abstract: Signals from the microenvironment are known to be critical for development, stem cell self-renewal and oncogenic progression. Although some niche-driven signals that promote cancer progression have been identified1,2,3,4,5, concerted efforts to map disease-relevant microenvironmental ligands of cancer stem cell receptors have been lacking. Here, we use temporal single-cell RNA-sequencing (scRNA-seq) to identify molecular cues from the bone marrow stromal niche that engage leukaemia stem-enriched cells (LSCs) during oncogenic progression. We integrate these data with our human LSC RNA-seq and in vivo CRISPR screen of LSC dependencies6 to identify LSC–niche interactions that are essential for leukaemogenesis. These analyses identify the taurine–taurine transporter (TAUT) axis as a critical dependency of aggressive myeloid leukaemias. We find that cysteine dioxygenase type 1 (CDO1)-driven taurine biosynthesis is restricted to osteolineage cells, and increases during myeloid disease progression. Blocking CDO1 expression in osteolineage cells impairs LSC growth and improves survival outcomes. Using TAUT genetic loss-of-function mouse models and patient-derived acute myeloid leukaemia (AML) cells, we show that TAUT inhibition significantly impairs in vivo myeloid leukaemia progression. Consistent with elevated TAUT expression in venetoclax-resistant AML, TAUT inhibition synergizes with venetoclax to block the growth of primary human AML cells. Mechanistically, our multiomic approaches indicate that the loss of taurine uptake inhibits RAG-GTP dependent mTOR activation and downstream glycolysis. Collectively, our work establishes the temporal landscape of stromal signals during leukaemia progression and identifies taurine as a key regulator of myeloid malignancies.

DOI: 10.1038/s41586-025-09018-7

Source: https://www.nature.com/articles/s41586-025-09018-7