The lysophospholipase D enzyme Gdpd3 is required to maintain chronic myelogenous leukaemia stem cells

Nat Commun. 2020 Sep 17;11(1):4681. doi: 10.1038/s41467-020-18491-9.

Abstract

Although advanced lipidomics technology facilitates quantitation of intracellular lipid components, little is known about the regulation of lipid metabolism in cancer cells. Here, we show that disruption of the Gdpd3 gene encoding a lysophospholipase D enzyme significantly decreased self-renewal capacity in murine chronic myelogenous leukaemia (CML) stem cells in vivo. Sophisticated lipidomics analyses revealed that Gdpd3 deficiency reduced levels of certain lysophosphatidic acids (LPAs) and lipid mediators in CML cells. Loss of Gdpd3 also activated AKT/mTORC1 signalling and cell cycle progression while suppressing Foxo3a/β-catenin interaction within CML stem cell nuclei. Strikingly, CML stem cells carrying a hypomorphic mutation of Lgr4/Gpr48, which encodes a leucine-rich repeat (LRR)-containing G-protein coupled receptor (GPCR) acting downstream of Gdpd3, displayed inadequate disease-initiating capacity in vivo. Our data showing that lysophospholipid metabolism is required for CML stem cell maintenance in vivo establish a new, biologically significant mechanism of cancer recurrence that is independent of oncogene addiction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Female
  • Forkhead Box Protein O3 / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
  • Lysophospholipids / metabolism
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Neoplasm Recurrence, Local / metabolism
  • Phosphoric Diester Hydrolases / genetics
  • Phosphoric Diester Hydrolases / metabolism*
  • Receptors, G-Protein-Coupled / genetics
  • Signal Transduction
  • Stem Cells / metabolism*
  • beta Catenin / metabolism

Substances

  • Forkhead Box Protein O3
  • FoxO3 protein, mouse
  • LGR4 protein, mouse
  • Lysophospholipids
  • Receptors, G-Protein-Coupled
  • beta Catenin
  • Mechanistic Target of Rapamycin Complex 1
  • Phosphoric Diester Hydrolases
  • alkylglycerophosphoethanolamine phosphodiesterase