Role of Lysophospholipid Metabolism in Chronic Myelogenous Leukemia Stem Cells

SIMPLE SUMMARY: In this review, I discuss our recent finding that lysophospholipid metabolism is essential for the maintenance of chronic myelogenous leukemia (CML) stem cells. Lysophospholipids have only one fatty acid chain and so are more hydrophilic than phospholipids, allowing them to act as lipid second messengers. We demonstrated that the stem cell quiescence and TKI resistance displayed by CML stem cells in vivo are sustained by the Gdpd3 enzyme involved in lysophospholipid metabolism. At the mechanistic level, Gdpd3 function allows lysophospholipid metabolism to suppress the AKT/mTORC1-mediated cell growth pathway while activating the stemness factors FOXO and β-catenin. Our results thus link lysophospholipid metabolism to CML stemness, and may thereby open up new therapeutic avenues to overcome CML relapse post-TKI therapy. ABSTRACT: It is well known that mature chronic myelogenous leukemia (CML) cells proliferate in response to oncogenic BCR–ABL1-dependent signaling, but how CML stem cells are able to survive in an oncogene-independent manner and cause disease relapse has long been elusive. Here, I put into the context of the broader literature our recent finding that lysophospholipid metabolism is essential for the maintenance of CML stem cells. I describe the fundamentals of lysophospholipid metabolism and discuss how one of its key enzymes, Glycerophosphodiester Phosphodiesterase Domain Containing 3 (Gdpd3), is responsible for maintaining the unique characteristics of CML stem cells. I also explore how this knowledge may be exploited to devise novel therapies for CML patients.