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Journal Articles Stem Cells / Stem Cells (Miamisburg) Year : 2012

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

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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.

Dates and versions

inserm-00726849 , version 1 (31-08-2012)

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Cite

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