Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Department of Hematology, Shanghai Zhaxin Hospital, Shanghai 200434, China.
Sci Adv. 2021 Mar 10;7(11). doi: 10.1126/sciadv.abd6280. Print 2021 Mar.
How metabolic status controls the fates of different types of leukemia cells remains elusive. Using a SoNar-transgenic mouse line, we demonstrated that B cell acute lymphoblastic leukemia (B-ALL) cells had a preference in using oxidative phosphorylation. B-ALL cells with a low SoNar ratio (SoNar-low) had enhanced mitochondrial respiration capacity, mainly resided in the vascular niche, and were enriched with more functional leukemia-initiating cells than that of SoNar-high cells in a murine B-ALL model. The SoNar-low cells were more resistant to cytosine arabinoside (Ara-C) treatment. cyclic adenosine 3',5'-monophosphate response element-binding protein transactivated pyruvate dehydrogenase complex component X and cytidine deaminase to maintain the oxidative phosphorylation level and Ara-C-induced resistance. SoNar-low human primary B-ALL cells also had a preference for oxidative phosphorylation. Suppressing oxidative phosphorylation with several drugs sufficiently attenuated Ara-C-induced resistance. Our study provides a unique angle for understanding the potential connections between metabolism and B-ALL cell fates.
代谢状态如何控制不同类型白血病细胞的命运仍然难以捉摸。使用 SoNar 转基因小鼠系，我们证明 B 细胞急性淋巴细胞白血病（B-ALL）细胞优先使用氧化磷酸化。SoNar 比值低（SoNar-low）的 B-ALL 细胞具有增强的线粒体呼吸能力，主要位于血管壁龛中，并且在小鼠 B-ALL 模型中比 SoNar-high 细胞具有更多功能的白血病起始细胞。SoNar-low 细胞对阿糖胞苷（Ara-C）治疗的抵抗力更强。环腺苷酸 3'，5'-单磷酸反应元件结合蛋白转激活丙酮酸脱氢酶复合物 X 和胞苷脱氨酶以维持氧化磷酸化水平和 Ara-C 诱导的耐药性。SoNar-low 人原发性 B-ALL 细胞也偏爱氧化磷酸化。用几种药物抑制氧化磷酸化足以减弱 Ara-C 诱导的耐药性。我们的研究为理解代谢与 B-ALL 细胞命运之间的潜在联系提供了一个独特的视角。
