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

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.

Automated summary

The study identified KDSR as essential for leukemia cell maintenance, with its loss causing apoptosis, cell cycle arrest, and aberrant ER structure. Transcriptomic analysis revealed the crucial role of KDSR in maintaining the unfolded protein response in ER. Mechanistically, depletion of KDSR led to dysregulation of UPR checkpoint proteins and accumulation of 3-ketodihydrosphingosine, pointing to the therapeutic potential of targeting sphingolipid metabolism and ER homeostasis in leukemia treatment.