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

Kazuhito Naka (), Ryosuke Ochiai, Eriko Matsubara, Chie Kondo, Kyung-Min Yang, Takayuki Hoshii, Masatake Araki, Kimi Araki, Yusuke Sotomaru, Ko Sasaki, Kinuko Mitani, Dong-Wook Kim, Akira Ooshima and Seong-Jin Kim
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Kazuhito Naka: Hiroshima University
Ryosuke Ochiai: Pharmaceuticals and Life Sciences Division, Shimadzu Techno-Research
Eriko Matsubara: Pharmaceuticals and Life Sciences Division, Shimadzu Techno-Research
Chie Kondo: Pharmaceuticals and Life Sciences Division, Shimadzu Techno-Research
Kyung-Min Yang: Seoul National University
Takayuki Hoshii: Chiba University
Masatake Araki: Kumamoto University
Kimi Araki: Kumamoto University
Yusuke Sotomaru: Hiroshima University
Ko Sasaki: Dokkyo Medical University School of Medicine
Kinuko Mitani: Dokkyo Medical University School of Medicine
Dong-Wook Kim: The Catholic University of Korea
Akira Ooshima: Seoul National University
Seong-Jin Kim: Seoul National University

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18491-9

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