Heterogeneous sensitivity of human Acute Myeloid Leukemia to ß-catenin down-modulation

Dysregulation of the Wnt/ß-catenin pathway has been observed in various malignancies, including acute myeloid leukemia (AML), where the over-expression of ß-catenin is an independent adverse prognostic factor. ß-catenin was found up-regulated in the vast majority of AML samples and more frequently localized in the nucleus of leukemic stem cells compared to normal bone marrow CD34(+) cells. The knockdown of ß-catenin, using a short hairpin RNA (shRNA) lentiviral approach, accelerates ATRA-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 ß-catenin was silenced. However when studying primary AML cells, despite effective down-regulation of ß-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 demonstrate that despite a frequent ß-catenin up-regulation in AML, leukemia initiating cells might not be ‘addicted’ to this pathway and thus targeted therapy against ß-catenin might not be successful in all patients.