Journal
STEM CELLS
Volume 30, Issue 8, Pages 1597-1610Publisher
WILEY
DOI: 10.1002/stem.1157
Keywords
Focal adhesion kinase; Leukemia; Splice variants; Stem cells; Wnt
Categories
Funding
- Association pour la Recherche sur le Cancer [8407]
- Institut National du Cancer [07/3D1616/IABC-23-8/NC-NG]
- Conseil Regional Midi-Pyrenees
- RTRS (axe cibles therapeutiques des lymphomes et des leucemies'')
- Agence nationale de la recherche [ANR-05-2_42589]
- Agence pour la Recherche sur le Cancer [A05/3/3138]
- Canadian Cancer Society Research Institute
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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 down-stream activation of beta-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 beta-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 CELLS 2012; 30:1597-1610
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