Abstract
Simple SummaryIn 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.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.
Highlights
The pro-proliferative signaling triggered by BCR–ABL1 can be blocked by tyrosine kinase inhibitors (TKIs), which has dramatically improved the prognosis of many chronic myelogenous leukemia (CML) patients [2]
While it is still unknown exactly how Glycerophosphodiester Phosphodiesterase Domain Containing 3 (Gdpd3) is involved in producing lipid mediators, these results suggest that at least some important messengers originate from lysophospholipid metabolism
We found that expression levels of the Lpar4/Gpr23 gene were decreased in Gdpd3-deficient LT-CML stem cells compared to WT-LT-CML stem cells
Summary
Chronic myeloid leukemia (CML) arises when the BCR–ABL1 fusion oncogene forms and is activated in hematopoietic stem cells (HSCs) [1,2]. The pro-proliferative signaling triggered by BCR–ABL1 can be blocked by tyrosine kinase inhibitors (TKIs), which has dramatically improved the prognosis of many CML patients [2]. The first such TKI was imatinib mesylate (imatinib), and secondgeneration TKIs include dasatinib, nilotinib and bosutinib. It turns out that the CML stem cells that generate most mature CML cells are responsible for disease relapse post-TKI therapy [6,7,8]. After TKI therapy is stopped, the surviving CML stem cells emerge from quiescence and give rise to a new cadre of mature CML cells. It is reportedly known that several factors within the bone marrow microenvironmental niche are responsible for the maintenance of self-renewal capacity in CML stem cells in a non-cell autonomous manner [6,7,8]
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