Expression of beta-catenin by acute myeloid leukemia cells predicts enhanced clonogenic capacities and poor prognosis.
Activation of the Wnt/beta-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 beta-catenin was correlated to clonogenic capacity also in the acute myeloid leukemia (AML) setting. Eighty-two patients were retrospectively evaluated for beta-catenin expression by Western blot. beta-Catenin was expressed (although at various protein levels) in 61% of patients, and was undetectable in the remaining cases. In our cohort, beta-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, beta-catenin appeared as a new independent prognostic factor predicting poor event-free survival and shortened overall survival (both with P<0.05). Furthermore, variations in beta-catenin protein levels were dependent on post-transcriptional mechanisms involving the Wnt/beta-catenin pathway only in leukemic cells. Indeed, beta-catenin negative leukemic cells were found to increase beta-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.
Ysebaert
L
L
NSERM U563, Centre de Physiopathologie Toulouse Purpan (CPTP), Département Oncogenèse et Signalisation dans les cellules Hématopoïétiques, CHU Purpan, Toulouse Cedex, France. ysebaert.l@chu-toulouse.fr
Chicanne
G
G
Demur
C
C
De Toni
F
F
Prade-Houdellier
N
N
Ruidavets
J-B
JB
Mansat-De Mas
V
V
Rigal-Huguet
F
F
Laurent
G
G
Payrastre
B
B
Manenti
S
S
Racaud-Sultan
C
C