Open AccessHeterogeneous sensitivity of human acute myeloid leukemia to β-catenin down-modulation
Author(s) -
Arnaud Gandillet,
Sophie Park,
François Lassailly,
Emmanuel Griessinger,
Jacques Vargaftig,
Andrew Filby,
T. Andrew Lister,
Dominique Bonnet
Publication year - 2011
Publication title -
leukemia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.539
H-Index - 192
eISSN - 1476-5551
pISSN - 0887-6924
DOI - 10.1038/leu.2011.17
Subject(s) - cancer research , small hairpin rna , myeloid leukemia , wnt signaling pathway , leukemia , catenin , downregulation and upregulation , stem cell , cd34 , haematopoiesis , biology , bone marrow , gene knockdown , tretinoin , retinoic acid , immunology , cell culture , medicine , microbiology and biotechnology , signal transduction , biochemistry , gene , genetics
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.