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Identification and Characterisation of Lgr4/Β-Catenin Signalling in Acute Myeloid Leukaemic Stem Cells

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Identification and Characterisation of Lgr4/Β-Catenin Signalling in Acute Myeloid Leukaemic Stem Cells Identification and Characterisation of Lgr4/β-catenin Signalling in Acute Myeloid Leukaemic Stem Cells Hangyu Yi Bachelor of Medical Science (Honours Class 1) Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy School of Women’s and Children’s Health Faculty of Medicine University of New South Wales February 2016 PLEASE TYPE THE UNIVERSITY OF NEW SOUTH WALES Thesis/Dissertation Sheet Surname or Family name: Yi First name: Hangyu Other name/s: Abbreviation for degree as given in the University calendar: PhD School: School of Women’s and Children’s Health Faculty: Medicine Title: Identification and characterisation of Lgr4/β- catenin signalling in acute myeloid leukaemic stem cells Abstract 350 words maximum: (PLEASE TYPE) Acute myeloid leukaemia (AML) is a deadly form of leukaemia resulting in the highest number of leukaemia-associated deaths. The high mortality rate is due to frequent relapse caused by the persistence of drug-resistant leukaemic stem cells (LSCs). We have previously demonstrated an essential role for β-catenin signalling in regulating LSCs in AML. Leucine-rich repeat containing G protein-coupled receptor 4 (Lgr4) has recently been identified as the receptor for R-spondin (Rspo) proteins to activate β-catenin. This study showed that Rspo2/Rspo3 cooperating with Wnt3a potently potentiated β-catenin activation in haematopoietic stem cell (HSC)-derived pre-LSCs. Overexpression of Lgr4 augmented activation of Wnt/β-catenin signalling and promoted leukaemogenesis in vivo. Inhibition of Lgr4 reduced β-catenin activity, completely abolished Rspo3/Wnt3a/β-catenin signalling and prevented leukaemia development. A microarray experiment of 104 AML patient samples showed that high Lgr4 expression was associated with poor outcomes of AML patients. Altogether, these findings provide strong evidence demonstrating Lgr4 to be a critical regulator of β-catenin signalling in AML. Gene expression profiling identified Rgs1 (regulator of G protein signalling 1) to be a major component of Lgr4 signalling. Rgs1 has been shown to bind directly to G protein subunits Gαq and Gαi (Moratz et al., J Immunol, 2000), and treatment of pre-LSCs with Gαq and Gαi inhibitors indicated Gαq to be a key downstream effector of Lgr4/Rgs1 signalling. Further functional studies showed that Gαq knockdown reduced β-catenin expression, attenuated the effect of Wnt3a/Rspo3-potentiated β-catenin activation and impaired LSC self-renewal, recapitulating the role of Lgr4 in LSC regulation. These data support the view that Gαq is an integral component of Lgr4 signalling in LSCs. Gene expression analysis also showed that Lgr4 knockdown increased expression of Gadd45a (growth arrest and DNA damage- inducible gene) and repressed several mitochondrial associated genes. Functional studies showed that Gadd45a deletion significantly increased in vivo LSC self-renewal and enhanced AML progression. Blockade of Lgr4 signalling inhibited mitochondrial energy metabolism, on which LSCs rely for survival. Collectively, this study has identified a novel Wnt3a/Rspo2/Rspo3-Lgr4Gαqβ-catenin signalling pathway governing LSCs and interference with components of this pathway may represent a promising therapeutic approach for eradicating LSCs in AML. Declaration relating to disposition of project thesis/dissertation I hereby grant to the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or in part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all property rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstracts International (this is applicable to doctoral theses only). …………………………………………………… ……………………………………..……… ……….……………………...… Signature Witness Date The University recognises that there may be exceptional circumstances requiring restrictions on copying or conditions on use. Requests for restriction for a period of up to 2 years must be made in writing. Requests for a longer period of restriction may be considered in exceptional circumstances and require the approval of the Dean of Graduate Research. FOR OFFICE USE ONLY Date of completion of requirements for Award: THIS SHEET IS TO BE GLUED TO THE INSIDE FRONT COVER OF THE THESIS Originality statement ‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.’ Signed ……………………………………… Date ……………………………………… i Copyright statement ‘I hereby grant the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all proprietary rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstract International (this is applicable to doctoral theses only). I have either used no substantial portions of copyright material in my thesis or I have obtained permission to use copyright material; where permission has not been granted I have applied/will apply for a partial restriction of the digital copy of my thesis or dissertation.' Signed ……………………………………… Date ……………………………………… Authenticity statement ‘I certify that the Library deposit digital copy is a direct equivalent of the final officially approved version of my thesis. No emendation of content has occurred and if there are any minor variations in formatting, they are the result of the conversion to digital format.’ Signed ……………………………………… Date ……………………………………… ii Abstract Acute myeloid leukaemia (AML) is a deadly form of leukaemia resulting in the highest number of leukaemia-associated deaths. The high mortality rate is due to frequent relapse caused by the persistence of drug-resistant leukaemic stem cells (LSCs). We have previously demonstrated an essential role for β-catenin signalling in regulating LSCs in AML. Leucine-rich repeat containing G protein-coupled receptor 4 (Lgr4) has recently been identified as the receptor for R-spondin (Rspo) proteins to activate β-catenin. This study showed that Rspo2/Rspo3 cooperating with Wnt3a potently potentiated β-catenin activation in haematopoietic stem cell (HSC)-derived pre-LSCs. Overexpression of Lgr4 augmented activation of Wnt/β-catenin signalling and promoted leukaemogenesis in vivo. Inhibition of Lgr4 reduced β-catenin activity, completely abolished Rspo3/Wnt3a/β-catenin signalling and prevented leukaemia development. A microarray experiment of 104 AML patient samples showed that high Lgr4 expression was associated with poor outcomes of AML patients. Altogether, these findings provide strong evidence demonstrating Lgr4 to be a critical regulator of β-catenin signalling in AML. Gene expression profiling identified Rgs1 (regulator of G protein signalling 1) to be a major component of Lgr4 signalling. Rgs1 has been shown to bind directly to G protein subunits Gαq and Gαi (Moratz et al., J Immunol, 2000), and treatment of pre-LSCs with Gαq and Gαi inhibitors indicated Gαq to be a key downstream effector of Lgr4/Rgs1 signalling. Further functional studies showed that Gαq knockdown reduced β-catenin expression, attenuated the effect of Wnt3a/Rspo3-potentiated β-catenin activation and impaired LSC self-renewal, recapitulating the role of Lgr4 in LSC regulation. These data support the view that Gαq is an integral component of Lgr4 signalling in LSCs. iii Gene expression analysis also showed that Lgr4 knockdown increased expression of Gadd45a (growth arrest and DNA damage-inducible gene) and repressed several mitochondrial associated genes. Functional studies showed that Gadd45a deletion significantly increased in vivo LSC self-renewal and enhanced AML progression. Blockade of Lgr4 signalling inhibited mitochondrial energy metabolism, on which LSCs rely for survival. Collectively, this study has identified a novel Wnt3a/Rspo2/Rspo3-Lgr4Gαqβ- catenin signalling pathway governing LSCs and interference with components of this pathway may represent a promising therapeutic approach for eradicating LSCs in AML. iv 1 Introduction ............................................................................................................ 1 1.1 Acute myeloid leukaemia .................................................................................. 2 1.1.1 Heterogeneity of AML ............................................................................... 4 1.1.1.1 Favourable genetic features ................................................................
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