Focal adhesion kinase splice variants maintain primitive acute myeloid leukemia cells through altered wnt signaling.

Mathieu Despeaux 1 Gaëtan Chicanne 2 Evelyne Rouer 3 Fabienne De Toni-Costes 4 Jessica Bertrand 1 Véronique Mansat-De Mas 4, 5 Nathalie Vergnolle 1 Connie Eaves 6 Bernard Payrastre 2 Jean-Antoine Girault 3 Claire Racaud-Sultan 1, *
* Auteur correspondant
1 CPTP - Centre de Physiopathologie de Toulouse Purpan
2 I2MC - Institut des Maladies Métaboliques et Cardiovasculaires
3 Institut du Fer à Moulin
4 CRCT - Centre de Recherche en Cancérologie de Toulouse
5 Laboratoire d'Hématologie [Purpan]
6 Terry Fox Laboratory
Abstract : Focal adhesion kinase (FAK) activity contributes to many advanced cancer phenotypes, but little is known about its role in human acute myeloid leukemia (AML). Here, we show that FAK splice variants are abnormally expressed in the primitive leukemic cells of poor prognosis AML patients. In the CD34(+) 38(-) 123(+) long-term culture-initiating cell-enriched leukemic cells of these patients, FAK upregulates expression of Frizzled-4 and phosphorylates Pyk2 to enable the required association of Pyk2 with the Wnt5a/Frizzled-4/LRP5 endocytosis complex and downstream activation of β-catenin, thereby replacing the Wnt3a-controlled canonical pathway used by normal hematopoietic stem cells. Transduction of primitive normal human hematopoietic cells with FAK splice variants induces a marked increase in their clonogenic activity and signaling via the Wnt5a-controlled canonical pathway. Targeting FAK or β-catenin efficiently eradicates primitive leukemic cells in vitro suggesting that FAK could be a useful therapeutic target for improved treatment of poor prognosis AML cases. STEM CELLS2012;30:1597-1610.
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Stem Cells / Stem Cells (Miamisburg), Alphamed Press, 2012, 30 (8), pp.1597-610. 〈10.1002/stem.1157〉
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http://www.hal.inserm.fr/inserm-00726849
Contributeur : Marie Francoise Simon <>
Soumis le : vendredi 31 août 2012 - 13:50:45
Dernière modification le : jeudi 4 octobre 2018 - 09:50:10

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Mathieu Despeaux, Gaëtan Chicanne, Evelyne Rouer, Fabienne De Toni-Costes, Jessica Bertrand, et al.. Focal adhesion kinase splice variants maintain primitive acute myeloid leukemia cells through altered wnt signaling.. Stem Cells / Stem Cells (Miamisburg), Alphamed Press, 2012, 30 (8), pp.1597-610. 〈10.1002/stem.1157〉. 〈inserm-00726849〉

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