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ACUTE MYELOID LEUKEMIA

3-Ketodihydrosphingosine reductase maintains ER homeostasis and unfolded protein response in leukemia

Leukemia volume 36, pages 100–110 (2022)Cite this article

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Abstract

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.

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Fig. 1: Sphingolipid metabolism focused CRISPR/Cas9 screens in leukemia.
Fig. 2: KDSR is essential for leukemia cells.
Fig. 3: KDSR depletion dysregulates the UPR pathway and ER structure.
Fig. 4: Accumulation of KDS after KDSR depletion dysregulates the UPR pathway and ER structure.
Fig. 5: Targeting KDSR sensitizes the leukemia cells to ER stress inducer tunicamycin.
Fig. 6: KDS synergizes with tunicamycin in leukemia and lymphoma.

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Data availability

Datasets can be found in Tables S1 and S2. RNA-Seq data generated in this study is available in the Gene Expression Omnibus (GEO: GSE167688). Other data that support the findings of this study are available from the corresponding author upon reasonable request.

Code availability

The computational codes/tool packages used in this study are available through developers and venders, including Genetic Perturbation Platform, CLC Main Workbench, Bowtie2, and Gaussian kernel smoothing in R.

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Acknowledgements

This work was supported by the American Society of Hematology (ASH Scholar Award to C.-W.C.), Alex’s Lemonade Stand Foundation (ALSF Innovation Award to C.-W.C.), National Institutes of Health Grants CA197498, CA233691, CA236626 (to C.-W.C.), Graduate Academic Exchange Scholarship of Fujian Medical University (to Q.L.), and Riggs-Union International Exchange Scholarship of Fujian Medical University Union Hospital (to Q.L.). Research reported in this publication included work performed in the City of Hope’s Mass Spectrometry and Proteomics Core Facility (Dr. Gabriel Gugiu) and Electron Microscopy Core Facility (Drs. Zhuo Li and Ricardo Zerda) supported by the National Cancer Institute of the National Institutes of Health P30 Grant CA033572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Fujian Provincial Key Laboratory on Hematology, Department of Hematology, Fujian Institute of Hematology, Fujian Medical University Union Hospital, Fuzhou, China

    Qiao Liu & Shao-Yuan Wang

  2. Union Clinical Medical College, The Graduate School of Fujian Medical University, Fuzhou, China

    Qiao Liu & Shao-Yuan Wang

  3. Department of Systems Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA

    Qiao Liu, Anthony K. N. Chan, Wen-Han Chang, Lu Yang, Sheela Pangeni Pokharel, Kazuya Miyashita, Nicole Mattson, Xiaobao Xu, Mingli Li, Wei Lu & Chun-Wei Chen

  4. Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA

    Ren-Jang Lin

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Contributions

QL, AKNC, W-HC, LY, SPP, KM, NM, XX, ML performed the experiments; QL, LY, AKNC, WL and C-WC analyzed the data; RJL, SYW, and C-WC provided conceptual input; QL, RJL, and C-WC wrote the paper; SYW and C-WC conceived and supervised the study.

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Correspondence to Shao-Yuan Wang or Chun-Wei Chen.

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Liu, Q., Chan, A.K.N., Chang, WH. et al. 3-Ketodihydrosphingosine reductase maintains ER homeostasis and unfolded protein response in leukemia. Leukemia 36, 100–110 (2022). https://doi.org/10.1038/s41375-021-01378-z

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