Focal Adhesion Kinase Splice Variants Maintain Primitive Acute Myeloid Leukemia Cells Through Altered Wnt Signaling
Focal Adhesion Kinase Splice Variants Maintain Primitive Acute Myeloid Leukemia Cells Through Altered Wnt Signaling
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DOI：
10.1002/stem.1157
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发表时间：
2012-08-01
期刊：
影响因子：
5.2
通讯作者：
Racaud-Sultan, Claire
中科院分区：
文献类型：
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作者：
Despeaux, Mathieu;Chicanne, Gaetan;Racaud-Sultan, Claire
粘着斑激酶 (FAK) 活性导致许多晚期癌症表型，但对其在人类急性髓系白血病 (AML) 中的作用知之甚少。在这里，我们发现 FAK 剪接变体在预后不良的 AML 患者的原始白血病细胞中异常表达。在这些患者的 CD34(+)38(-)123(+) 长期培养起始细胞富集的白血病细胞中，FAK 上调 Frizzled-4 的表达并磷酸化 Pyk2，以使 Pyk2 与 Wnt5a/Frizzled-4/LRP5 内吞复合物和下游 β-catenin 激活所需的关联，从而取代 正常造血干细胞使用 Wnt3a 控制的经典途径。用 FAK 剪接变体转导原始正常人类造血细胞可诱导其克隆形成活性和通过 Wnt5a 控制的经典途径的信号传导显着增加。靶向 FAK 或 β-连环蛋白可在体外有效地根除原始白血病细胞，这表明 FAK 可能是改善预后不良 AML 病例治疗的有用治疗靶点。干细胞2012； 30:1597-1610
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