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

Abstract

Activation of the Wnt/b-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 b-catenin was correlated to clonogenic capacity also in the acute myeloid leukemia (AML) setting. Eighty-two patients were retrospectively evaluated for b-catenin expression by Western blot. b-Catenin was expressed (although at various protein levels) in 61% of patients, and was undetectable in the remaining cases. In our cohort, b-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 replating assay. In survival analyses, b-catenin appeared as a new independent prognostic factor predicting poor event-free survival and shortened overall survival (both with Po0.05). Furthermore, variations in b-catenin protein levels were dependent on post-transcriptional mechanisms involving the Wnt/ b-catenin pathway only in leukemic cells. Indeed, b-catenin negative leukemic cells were found to increase b-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.

The emerging role of Wnt signaling in the pathogenesis of acute myeloid leukemia

“…119 b-Catenin, the key regulator of the Wnt pathway, is expressed at various protein levels in AML patients. 120,121 b-Catenin protein levels in AML cells differ from mRNA levels indicating translational and/or post-translational regulation by the Wnt pathway. b-Catenin expression was correlated with the clonogenic proliferation of AML-colony forming cells in methylcellulose, and more strikingly with self-renewal of leukemic cells, as assessed in vitro by a replating assay.…”

Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia

“…GSK-3b activity seems also important for adhesion and Wnt-pathway b-catenin expression and drug resistance in AML cells. 142,143 b-Catenin expression in AML cells predicts enhanced clonogenic capacities and is associated with a poor prognosis. 143 Thus, GSK-3b also plays key roles in regulating proliferative loops involved in malignant transformation of hematopoietic cells.…”

Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy

“…Elevated b-catenin expression is also associated with a poor event-free survival and shortened overall survival. 174 Targeting of various components in this pathway (for example, Flt-3) may inhibit leukemic stem cell growth. Indeed the Flt-3 inhibitor CEP-701 inhibited the engraftment of FLT3/ITD stem cells.…”