Visit our Expo - Redox and Inflammation signaling 2012

V. Phosphatases as key cell signaling intermediates Poster V, 3
Cell adhesion to the extracellular matrix increases the proliferation of acute myeloid
leukemia (AML) cells and up-regulates the CDC25A phosphatase.
Anne Fernandez-Vidal, Loïc Ysebaert, Christine Didier, Stéphane Manenti.
Centre de physiopathologie Toulouse-Purpan, INSERM U563-IFR30, Département
« Oncogénèse et signalisation dans les cellules hématopoïétiques », CHU Purpan, 3 place
du Dr Baylac 31024 Toulouse Cedex 3, France. E-mail : fervidal@toulouse.inserm.fr.
Microenvironmental stimuli are key factors in normal and leukemic hematopoietic
differenciation. In this contexte, we investigated the influence of the major extracellular
matrix component, fibronectin, on the proliferative state of acute myeloid leukemia and
normal hematopoietic cells. Although fibronectin inhibited the proliferation rate of immature
normal CD34+ cells, it stimulated the proliferation of immature leukemic cells at similar
differentiation state (KG1a cell line). These data suggest that hematopoietic cells shift from a
negative to a positive proliferative response to cell adhesion during the leukemogenic
transformation process. As a general feature, we found that cell adhesion to fibronectin matrix
increases the proliferation of various cell lines. Importantly, we identified the dual specificity
phosphatase Cdc25A as a key effector of this effect. Indeed, adhesion to fibronectin of
leukemic cells dramatically up-regulates the cellular level of this protein, in good correlation
with the proliferative response. By contrast, Cdc25A protein down-regulation was observed in
normal CD34+ cells, nicely fitting with the inhibition of the proliferation observed in these
cells. Furthermore, siRNA- and pharmacological inhibitor-based experiments strongly suggest
that Cdc25A regulation in this context is indeed involved in the adhesion –dependent
proliferation process. Altogether, these data demonstrate for the first time an integrindependent
Cdc25A protein regulation, making of this cell cycle effector an important link
between extracellular stimuli and the cell cycle machinery. This also make of this phosphatase
and of its molecular regulators, a potential therapeutic target in the acute myeloid leukemia
pathologies.
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