Gaq signaling is required for the maintenance of MLL-AF9-induced acute myeloid leukemia

Lynch, Jacqueline; Yi, Hangyu; Casolari, Débora A.; Voli, Florida; Gonzales‐Aloy, Estrella; Fung, Tsz Kan; Liu, Bo; Brown, Anna L.; Liu, T; Haber, Michelle; Norris, Murray D.; Lewis, ID; So, Chintae; D’Andrea, Richard J.; Wang, Jenny

doi:10.1038/leu.2016.24

Cited by 9 publications

(8 citation statements)

References 16 publications

(17 reference statements)

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“…In support of this therapeutic rationale, we have recently shown an essential role for G protein subunit Gα q in the maintenance of AML LSCs [ 84 ]. By using both shRNA-mediated silencing and pharmacological inhibition, our study shows that Gα q regulates LSC growth and survival in vitro and in vivo , and controls β-catenin activity.…”

Section: The Diversity Of Gpcr Signaling Mechanismsmentioning

confidence: 99%

“…By using both shRNA-mediated silencing and pharmacological inhibition, our study shows that Gα q regulates LSC growth and survival in vitro and in vivo , and controls β-catenin activity. Using a commercially available Gα q inhibitor, GP-antagonist 2A, our data indicates that ex vivo pre-treatment of LSCs with the antagonist impairs their proliferative capacity in mouse bone marrow and prolongs mouse survival [ 84 ]. Therefore, further investigations into the therapeutic applicability of GP-antagonist 2A for the treatment of AML are significantly warranted.…”

Section: The Diversity Of Gpcr Signaling Mechanismsmentioning

confidence: 99%

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G Protein-Coupled Receptor Signaling in Stem Cells and Cancer

Lynch

Wang

2016

IJMS

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G protein-coupled receptors (GPCRs) are a large superfamily of cell-surface signaling proteins that bind extracellular ligands and transduce signals into cells via heterotrimeric G proteins. GPCRs are highly tractable drug targets. Aberrant expression of GPCRs and G proteins has been observed in various cancers and their importance in cancer stem cells has begun to be appreciated. We have recently reported essential roles for G protein-coupled receptor 84 (GPR84) and G protein subunit Gαq in the maintenance of cancer stem cells in acute myeloid leukemia. This review will discuss how GPCRs and G proteins regulate stem cells with a focus on cancer stem cells, as well as their implications for the development of novel targeted cancer therapies.

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Section: The Diversity Of Gpcr Signaling Mechanismsmentioning

confidence: 99%

Section: The Diversity Of Gpcr Signaling Mechanismsmentioning

confidence: 99%

G Protein-Coupled Receptor Signaling in Stem Cells and Cancer

Lynch

Wang

2016

IJMS

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“…(110). However, in human oesophageal adenocarcinoma cells, ROCK2 is upstream of Nox5-derived ROS (111). These findings suggest that ROCK signalling is a redox-sensitive pathway and GPCR generation of ROS could play a major role in GPCR transactivation of TGFBR1 via ROCK signalling.…”

Section: The Role Of Nox/ros In Gpcr Transactivation Of Tgfbr1mentioning

confidence: 90%

GPCR transactivation signalling in vascular smooth muscle cells: role of NADPH oxidases and reactive oxygen species

et al. 2019

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The discovery and extension of G-protein-coupled receptor (GPCR) transactivation-dependent signalling has enormously broadened the GPCR signalling paradigm. GPCRs can transactivate protein tyrosine kinase receptors (PTKRs) and serine/threonine kinase receptors (S/TKRs), notably the epidermal growth factor receptor (EGFR) and transforming growth factor-β type 1 receptor (TGFBR1), respectively. Initial comprehensive mechanistic studies suggest that these two transactivation pathways are distinct. Currently, there is a focus on GPCR inhibitors as drug targets, and they have proven to be efficacious in vascular diseases. With the broadening of GPCR transactivation signalling, it is therefore important from a therapeutic perspective to find a common transactivation pathway of EGFR and TGFBR1 that can be targeted to inhibit complex pathologies activated by the combined action of these receptors. Reactive oxygen species (ROS) are highly reactive molecules and they act as second messengers, thus modulating cellular signal transduction pathways. ROS are involved in different mechanisms of GPCR transactivation of EGFR. However, the role of ROS in GPCR transactivation of TGFBR1 has not yet been studied. In this review, we will discuss the involvement of ROS in GPCR transactivation-dependent signalling.

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“…4,5 We and others have shown that MLL fusion proteins (e.g., MLL-AF9) can serve as an initiating event for oncogenic conversion of normal HSPC into pre-LSC, which subsequently acquire additional events upon transplantation into mice for the development of LSC. [4][5][6][7] The selfrenewal rate in a pre-leukemic clone determines subsequent tumorigenic potential in vivo. We have previously demonstrated that pre-LSC transformed from normal HSPC by MLL-AF9 have higher self-renewal potential and produce a more aggressive leukemia in mice with shorter latency than pre-LSC transformed by haematologica 2019; 104:e296…”

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confidence: 99%

“…Jianlong Wang6 and Jenny Y.Wang 1 1 Cancer and Stem Cell Biology Group, Children's Cancer Institute, University of New South Wales, Sydney, Australia; 2 Kids Cancer Alliance, Translational Cancer Research Centre for Kids, Cancer Institute New South Wales, Sydney, Australia; 3 Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, the University of Western Australia, Crawley, Australia; 4 Centre for Medical Research, The University of Western Australia, Crawley, Australia; 5 Children's Cancer Institute, University of New South Wales, Sydney, Australia and 6 Department of Cell, Developmental and Regenerative Biology, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA…”

mentioning

confidence: 99%