ORP4L Extracts and Presents PIP₂ from Plasma Membrane for PLCβ3 Catalysis: Targeting It Eradicates Leukemia Stem...

Leukemia stem cells (LSCs) are a rare subpopulation of abnormal hematopoietic stem cells (HSCs) that propagates leukemia and are responsible for the high frequency of relapse in therapies. Detailed insights into LSCs' survival will facilitate the identification of targets for therapeutic approaches. Here, we develop an inhibitor, LYZ-81, which targets ORP4L with high affinity and specificity and selectively eradicates LCSs in vitro and in vivo. ORP4L is expressed in LSCs but not in normal HSCs and is essential for LSC bioenergetics and survival. It extracts PIP₂ from the plasma membrane and presents it to PLCβ3, enabling IP₃ generation and subsequent Ca²⁺-dependent bioenergetics. LYZ-81 binds ORP4L competitively with PIP₂ and blocks PIP₂ hydrolysis, resulting in defective Ca²⁺ signaling. The results provide evidence that LSCs can be eradicated through the inhibition of ORP4L by LYZ-81, which may serve as a starting point of drug development for the elimination of LSCs to eventually cure leukemia.