Arnaud Gandillet

King's College London, Londinium, England, United Kingdom

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Publications (8)72.84 Total impact

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    ABSTRACT: At early stages of vertebrate ontogeny, blood and endothelial cells develop from a common mesodermal progenitor, the haemangioblast. Upon haematopoietic commitment, the haemangioblast generates blood precursors through populations of endothelial cells with haemogenic properties. Although several transcription factors have been implicated in haemangioblast differentiation, the precise mechanisms governing cell fate decisions towards the generation of haemogenic endothelium precursors remain largely unknown. Under defined conditions, embryonic stem (ES) cells can be differentiated into haemangioblast-like progenitors that faithfully recapitulate early embryonic haematopoiesis. Here, we made use of mouse ES cells as a model system to understand the role of SOX7, a member of a large family of transcription factors involved in a wide range of developmental processes. During haemangioblast differentiation, SOX7 is expressed in haemogenic endothelium cells and is downregulated in nascent blood precursors. Gain-of-function assays revealed that the enforced expression of Sox7 in haemangioblast-derived blast colonies blocks further differentiation and sustains the expression of endothelial markers. Thus, to explore the transcriptional activity of SOX7, we focused on the endothelial-specific adhesion molecule VE-cadherin. Similar to SOX7, VE-cadherin is expressed in haemogenic endothelium and is downregulated during blood cell formation. We show that SOX7 binds and activates the promoter of VE-cadherin, demonstrating that this gene is a novel downstream transcriptional target of SOX7. Altogether, our findings suggest that SOX7 is involved in the transcriptional regulation of genes expressed in the haemogenic endothelium and provide new clues to decipher the molecular pathways that drive early embryonic haematopoiesis.
    Development 05/2012; 139(9):1587-98. DOI:10.1242/dev.071282 · 6.46 Impact Factor
  • Tsz K Fung · Arnaud Gandillet · Chi W.E. So
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    ABSTRACT: Leukemia carrying mutation of the mixed-lineage leukemia (MLL) gene is particularly refractory to current treatment, and is associated with frequent relapse. We will review the biology of MLL leukemia, and explore the potential of targeting multiple signaling pathways deregulated in MLL leukemic stem cells (LSCs). Glycogen synthase kinase 3 (GSK3) plays a critical role in mediating Hox/MEIS1 transcriptional program and its inhibition shows promise in suppressing leukemia carrying MLL fusions or aberrant Hox expression. However, recent evidence indicates that GSK3 inhibition can be overcome by hyperactivation of the canonical Wnt signaling pathway in MLL LSCs, whereas suppression of β-catenin resensitizes MLL LSCs to the GSK3 inhibitor treatment. These results suggest a differential GSK3 dependence in different subsets of leukemic populations during disease development. On the basis of the results from preclinical model studies, a combination treatment targeting both GSK3 and the canonical Wnt signaling pathway emerges as a promising avenue to eradicate MLL LSCs. Future effort in identifying the key tractable components along these signaling pathways will be critical for the development of effective inhibitors to target this aggressive disease.
    Current opinion in hematology 04/2012; 19(4):280-6. DOI:10.1097/MOH.0b013e3283545615 · 3.97 Impact Factor
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    ABSTRACT: Dysregulation of the Wnt/β-catenin pathway has been observed in various malignancies, including acute myeloid leukemia (AML), where the overexpression of β-catenin is an independent adverse prognostic factor. β-catenin was found upregulated in the vast majority of AML samples and more frequently localized in the nucleus of leukemic stem cells compared with normal bone marrow CD34(+) cells. The knockdown of β-catenin, using a short hairpin RNA (shRNA) lentiviral approach, accelerates all-trans retinoic acid-induced differentiation and impairs the proliferation of HL60 leukemic cell line. Using in vivo quantitative tracking of these cells, we observed a reduced engraftment potential after xenotransplantation when β-catenin was silenced. However, when studying primary AML cells, despite effective downregulation of β-catenin we did not observe any impairment of their in vitro long-term maintenance on MS-5 stroma nor of their engraftment potential in vivo. Altogether, these results show that despite a frequent β-catenin upregulation in AML, leukemia-initiating cells might not be 'addicted' to this pathway and thus targeted therapy against β-catenin might not be successful in all patients.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2011; 25(5):770-80. DOI:10.1038/leu.2011.17 · 10.43 Impact Factor
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    ABSTRACT: Identification of molecular pathways essential for cancer stem cells is critical for understanding the underlying biology and designing effective cancer therapeutics. Here, we demonstrated that β-catenin was activated during development of MLL leukemic stem cells (LSCs). Suppression of β-catenin reversed LSCs to a pre-LSC-like stage and significantly reduced the growth of human MLL leukemic cells. Conditional deletion of β-catenin completely abolished the oncogenic potential of MLL-transformed cells. In addition, established MLL LSCs that have acquired resistance against GSK3 inhibitors could be resensitized by suppression of β-catenin expression. These results unveil previously unrecognized multifaceted functions of β-catenin in the establishment and drug-resistant properties of MLL stem cells, highlighting it as a potential therapeutic target for an important subset of AMLs.
    Cancer cell 12/2010; 18(6):606-18. DOI:10.1016/j.ccr.2010.10.032 · 23.52 Impact Factor
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    ABSTRACT: We have previously shown that Sox7 was transiently expressed at the onset of blood specification and was implicated in the regulation of cell survival, proliferation, and maturation of hematopoietic precursors. Here, we assessed, using embryonic stem cell differentiation as a model system, whether Sox17 and Sox18, 2 close homologs of Sox7, may act similarly to Sox7 at the onset of hematopoietic development. Sox18-enforced expression led to the enhanced proliferation of early hematopoietic precursors while blocking their maturation, phenotype highly reminiscent of Sox7-enforced expression. In striking contrast, Sox17-enforced expression dramatically increased the apoptosis of these early precursors. Similarly to Sox7, Sox18 was transiently expressed during early hematopoiesis, but its expression was predominantly observed in CD41(+) cells, contrasting with Sox7, mostly expressed in Flk1(+) cells. Conversely, Sox17 remained marginally expressed during blood specification. Overall, our data uncover contrasting effect and expression pattern for Sox18 and Sox17 at the onset of hematopoiesis specification.
    Blood 03/2010; 115(19):3895-8. DOI:10.1182/blood-2009-10-247395 · 10.45 Impact Factor
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    ABSTRACT: The molecular mechanisms that regulate the balance between proliferation and differentiation of precursors at the onset of hematopoiesis specification are poorly understood. By using a global gene expression profiling approach during the course of embryonic stem cell differentiation, we identified Sox7 as a potential candidate gene involved in the regulation of blood lineage formation from the mesoderm germ layer. In the present study, we show that Sox7 is transiently expressed in mesodermal precursors as they undergo specification to the hematopoietic program. Sox7 knockdown in vitro significantly decreases the formation of both primitive erythroid and definitive hematopoietic progenitors as well as endothelial progenitors. In contrast, Sox7-sustained expression in the earliest committed hematopoietic precursors promotes the maintenance of their multipotent and self-renewing status. Removal of this differentiation block driven by Sox7-enforced expression leads to the efficient differentiation of hematopoietic progenitors to all erythroid and myeloid lineages. This study identifies Sox7 as a novel and important player in the molecular regulation of the first committed blood precursors. Furthermore, our data demonstrate that the mere sustained expression of Sox7 is sufficient to completely alter the balance between proliferation and differentiation at the onset of hematopoiesis.
    Blood 10/2009; 114(23):4813-22. DOI:10.1182/blood-2009-06-226290 · 10.45 Impact Factor
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    ABSTRACT: Understanding how blood cells are generated is important from a biological perspective but also has potential implications in the treatment of blood diseases. Such knowledge could potentially lead to defining new conditions to amplify hematopoietic stem cells (HSCs) or could translate into new methods to produce HSCs, or other types of blood cells, from human embryonic stem cells or induced pluripotent stem cells. Additionally, as most key transcription factors regulating early hematopoietic development have also been implicated in various types of leukemia, understanding their function during normal development could result in a better comprehension of their roles during abnormal hematopoiesis in leukemia. In this review, we discuss our current understanding of the molecular and cellular mechanisms of blood development from the earliest hematopoietic precursor, the hemangioblast, a precursor for both endothelial and hematopoietic cell lineages.
    Journal of Molecular Medicine 10/2009; 88(2):167-72. DOI:10.1007/s00109-009-0554-0 · 5.11 Impact Factor
  • Guilherme Costa · Arnaud Gandillet · Georges Lacaud · Valerie Kouskoff
    Mechanisms of Development 08/2009; 126. DOI:10.1016/j.mod.2009.06.635 · 2.44 Impact Factor