Fujian Provincial Key Laboratory on Hematology, Department of Hematology, Fujian Institute of Hematology, Fujian Medical University Union Hospital, Fuzhou, China.
Union Clinical Medical College, The Graduate School of Fujian Medical University, Fuzhou, China.
Leukemia. 2022 Jan;36(1):100-110. doi: 10.1038/s41375-021-01378-z. Epub 2021 Aug 9.
Sphingolipids and their metabolic pathways have been implicated in disease development and therapeutic response; however, the detailed mechanisms remain unclear. Using a sphingolipid network focused CRISPR/Cas9 library screen, we identified an endoplasmic reticulum (ER) enzyme, 3-Ketodihydrosphingosine reductase (KDSR), to be essential for leukemia cell maintenance. Loss of KDSR led to apoptosis, cell cycle arrest, and aberrant ER structure. Transcriptomic analysis revealed the indispensable role of KDSR in maintaining the unfolded protein response (UPR) in ER. High-density CRISPR tiling scan and sphingolipid mass spectrometry pinpointed the critical role of KDSR's catalytic function in leukemia. Mechanistically, depletion of KDSR resulted in accumulated 3-ketodihydrosphingosine (KDS) and dysregulated UPR checkpoint proteins PERK, ATF6, and ATF4. Finally, our study revealed the synergism between KDSR suppression and pharmacologically induced ER-stress, underscoring a therapeutic potential of combinatorial targeting sphingolipid metabolism and ER homeostasis in leukemia treatment.
鞘脂及其代谢途径与疾病的发生发展和治疗反应有关；然而，其详细机制尚不清楚。我们利用鞘脂网络为靶点的 CRISPR/Cas9 文库筛选，鉴定出内质网（ER）酶 3-酮二氢鞘氨醇还原酶（KDSR）对于白血病细胞的维持是必需的。KDSR 的缺失导致细胞凋亡、细胞周期停滞和内质网结构异常。转录组分析揭示了 KDSR 在维持内质网未折叠蛋白反应（UPR）中的不可或缺的作用。高密度 CRISPR 平铺扫描和鞘脂质谱分析确定了 KDSR 的催化功能在白血病中的关键作用。在机制上，KDSR 的耗竭导致积累了 3-酮二氢鞘氨醇（KDS）和失调的 UPR 检查点蛋白 PERK、ATF6 和 ATF4。最后，我们的研究揭示了 KDSR 抑制与药理学诱导的 ER 应激之间的协同作用，强调了联合靶向鞘脂代谢和 ER 稳态在白血病治疗中的治疗潜力。
