Expression of β-catenin by acute myeloid leukemia cells predicts enhanced clonogenic capacities and poor prognosis

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Abstract
Activation of the Wnt/β-catenin pathway has recently been shown to be crucial to the establishment of leukemic stem cells in chronic myeloid leukemia. We sought to determine whether β-catenin was correlated to clonogenic capacity also in the acute myeloid leukemia (AML) setting. Eighty-two patients were retrospectively evaluated for β-catenin expression by Western blot. β-Catenin was expressed (although at various protein levels) in 61% of patients, and was undetectable in the remaining cases. In our cohort, β-catenin expression was correlated with the clonogenic proliferation of AML-colony forming cells (AML-CFC or CFU-L) in methylcellulose in the presence of 5637-conditioned medium, and more strikingly with self-renewing of leukemic cells, as assessed in vitro by a re-plating assay. In survival analyses, β-catenin appeared as a new independent prognostic factor predicting poor event-free survival and shortened overall survival (both with Pβ-catenin protein levels were dependent on post-transcriptional mechanisms involving the Wnt/β-catenin pathway only in leukemic cells. Indeed, β-catenin negative leukemic cells were found to increase β-catenin in response to Wnt3a agonist in contrast to normal counterparts. Altogether, our data pave the way to the evaluation of Wnt pathway inhibition as a new rationale for eradicating the clonogenic pool of AML cells.