Budgeting at the Ca²⁺ store: a PIP₍₂₎eline to starve LSCs?

The oxysterol-binding protein-related proteins (ORPs) have emerged as orchestrators of phosphatidylinositol-4,5-bisphosphate (PIP₂) and cholesterol trafficking to the plasma membrane (PM). In this scenario, recent studies raised the prospect of ORPs cooperative behavior in sustaining leukemia stem cells (LSCs) survival by remotely enhancing ER-mitochondria Ca²⁺ communication. At the apex of the signaling cascade, the aberrantly upregulated LSC-ORP4L fosters PM-PIP₂ extraction & cleavage, endoplasmic reticulum (ER)-Ca²⁺ release and mitochondrial energetics. The theoretical ember of draining fuel from the chemoresistant LSCs by restraining endoplasmic reticulum (ER)-mitochondria Ca²⁺ fluxes in a lipid-contingent fashion ensues. In light of relevant literature, this review briefly and critically discusses some key molecular ins & outs underlying such therapeutic opportunity in acute myeloid leukemia (AML).