Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia

Salik, Basit; Yi, Hangyu; Hassan, Nunki; Santiappillai, Nancy; Vick, Binje; Connerty, Patrick; Duly, Alastair; Trahair, Toby N.; Woo, Andrew; Beck, Dominik; Liu, Tao; Spiekermann, Karsten; Jeremias, Irmela; Wang, Jianlong; Kavallaris, Maria; Haber, Michelle; Norris, Murray D.; Liebermann, Dan A.; D’Andrea, Richard J.; Murriel, Christopher L.; Wang, Jenny

doi:10.1016/j.ccell.2020.05.014

Cited by 64 publications

(46 citation statements)

References 63 publications

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“…During the reviewing process, a paper demonstrating that Lgr4 is essential for self-renewal in acute myelogenous leukaemia (AML) stem cells was published 54 . The study supports our conclusion about the role of Lgr4 in maintenance of CML stem cells.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Methodsmentioning

confidence: 99%

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

et al. 2020

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“…CSCs display many characteristics of embryonic or tissue stem cells and often show continuous activation of highly conserved signaling pathways related to development and tissue homeostasis [126,127]. The Wnt/βcatenin signaling pathway is associated with regulating the pluripotency, self-renewal of stem cells and differentiation ability [1,128].…”

Section: Cancer Stem Cells -Wnt/β-catenin Signaling Pathway Inhibitorsmentioning

confidence: 99%

“…The Wnt/β-catenin signaling pathway, also called the canonical Wnt signaling pathway, is a conserved signaling axis participating in diverse physiological processes such as proliferation, differentiation, apoptosis, migration, invasion and tissue homeostasis [1][2][3]. Increasing evidence indicates that dysregulation of the Wnt/β-catenin cascade contributed to the development and progression of some solid tumors and hematological malignancies [4][5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Targeting the Wnt/β-catenin signaling pathway in cancer

2020

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The aberrant Wnt/β-catenin signaling pathway facilitates cancer stem cell renewal, cell proliferation and differentiation, thus exerting crucial roles in tumorigenesis and therapy response. Accumulated investigations highlight the therapeutic potential of agents targeting Wnt/β-catenin signaling in cancer. Wnt ligand/ receptor interface, β-catenin destruction complex and TCF/β-catenin transcription complex are key components of the cascade and have been targeted with interventions in preclinical and clinical evaluations. This scoping review aims at outlining the latest progress on the current approaches and perspectives of Wnt/β-catenin signaling pathway targeted therapy in various cancer types. Better understanding of the updates on the inhibitors, antagonists and activators of Wnt/β-catenin pathway rationalizes innovative strategies for personalized cancer treatment. Further investigations are warranted to confirm precise and secure targeted agents and achieve optimal use with clinical benefits in malignant diseases.

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“…Self-renewal is a key property of LSCs and its deregulation is responsible for leukemia initiation and progression, which could be targeted for LSC eradication. Several pathways controlling LSC self-renewal have been identified in AML, such as WNT/β-catenin signaling and G protein-coupled receptors including GPR84 and LGR4 [5,6,19,20].…”

Section: Self-renewal Signaling In Leukemia Stem Cellsmentioning

confidence: 99%

“…The discovery of LSCs not only as the origin but also the culprit of therapeutic resistance in AML is a milestone in our understanding of malignancy and thus targeting LSCs is a critical and challenging step in developing anticancer therapy [4]. Recent evidence has shown that aberrant activation of self-renewal pathways, such as WNT/β-catenin and RSPO3-LGR4 pathways, is essential for the initiation and development of LSCs [5,6], unveiling a potential target for curative therapies in AML.…”

Section: Introductionmentioning

confidence: 99%

Self-Renewal Pathways in Acute Myeloid Leukemia Stem Cells

Yang¹,

Hassan²,

Chen³

et al. 2021

Acute Leukemias

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Acute myeloid leukemia (AML) is a difficult-to-treat blood cancer. A major challenge in treating patients with AML is relapse, which is caused by the persistence of leukemia stem cells (LSCs). Self-renewal is a defining property of LSCs and its deregulation is crucial for re-initiating a new leukemia after chemotherapy. Emerging therapeutic agents inhibiting aberrant self-renewal pathways, such as anti-RSPO3 monoclonal antibody discovered in our recent study, present significant clinical potential that may extend beyond the scope of leukemogenesis. In this chapter, we provide an overview of normal and malignant hematopoietic stem cells, discuss current treatments and limitations, and review key self-renewal pathways and potential therapeutic opportunities in AML.

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Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia

Cited by 64 publications

References 63 publications

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

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

Targeting the Wnt/β-catenin signaling pathway in cancer

Self-Renewal Pathways in Acute Myeloid Leukemia Stem Cells

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