Role of Lysophospholipid Metabolism in Chronic Myelogenous Leukemia Stem Cells

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.

Keywords: CML stemness; Foxo3a; Gdpd3; lysophospholipid.

Figure 1

Lipid metabolism in CML stem cells. Glycerophospholipids (phospholipids), which organize the lipid bilayer in a cell’s plasma membrane, are synthesized from lysophosphatidic acids (LPAs). LPAs originate from glycerol 3-phosphate (G3P) via the Kennedy pathway (de novo pathway). Phospholipids are converted to lysophospholipids via the Lands’ cycle (remodeling pathway), which can reverse to produce a wide variety of phospholipids. Lysophospholipids are recycled back into LPAs by lysophospholipase D enzymes such as Gdpd3. Whereas phospholipids have two hydrophobic fatty acid chains, lysophospholipids and LPAs have only one fatty acid chain. Thus, lysophospholipids and LPAs are more hydrophilic than phospholipids and can act as lipid second messengers. We recently demonstrated that CML stemness in vivo depends on Gdpd3 and its function in lysophospholipid metabolism [14].

Figure 2

Regulation of CML stemness is independent of BCR–ABL1 oncogenic signaling. In the vast majority of mature CML cells, cell proliferation is driven by BCR–ABL1-mediated activation of the PI3K–Akt–mTORC1 signaling pathway. CML stem cells are able to maintain stem cell quiescence despite possessing the oncogene and so are TKI resistant. We have shown that Gdpd3 and lysophospholipid metabolism are essential for maintaining CML stem cell functions in vivo. Elevated lysophospholipid metabolism contributes to CML stemness by regulating an interaction between active Foxo3a and β-catenin (although the exact mechanism remains unclear). It is possible that Gdpd3-mediated lysophospholipid metabolism: (1) suppresses Akt via an LPA–LPARs pathway; (2) contributes to the biosynthesis of lipid mediators; and/or (3) participates in a gene expression program involving Gdpd3 and GPCRs by FOXO/β-catenin. Targeting any one of these elements of lysophospholipid metabolism specific to CML stem cells might provide fresh therapies to overcome disease relapse in many CML patients.