Arnaud Gandillet

London Research Institute, Londinium, England, United Kingdom

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Publications (3)40.65 Total impact

  • 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. · 5.19 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. · 10.16 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. · 25.29 Impact Factor