Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Blood. 2012 Sep 27;120(13):2669-78. doi: 10.1182/blood-2011-08-375873. Epub 2012 Jul 17.
Intracellular mechanism(s) that contribute to promiscuous signaling via oncogenic KIT in systemic mastocytosis and acute myelogenous leukemia are poorly understood. We show that SHP2 phosphatase is essential for oncogenic KIT-induced growth and survival in vitro and myeloproliferative disease (MPD) in vivo. Genetic disruption of SHP2 or treatment of oncogene-bearing cells with a novel SHP2 inhibitor alone or in combination with the PI3K inhibitor corrects MPD by disrupting a protein complex involving p85α, SHP2, and Gab2. Importantly, a single tyrosine at position 719 in oncogenic KIT is sufficient to develop MPD by recruiting p85α, SHP2, and Gab2 complex to oncogenic KIT. Our results demonstrate that SHP2 phosphatase is a druggable target that cooperates with lipid kinases in inducing MPD.
导致系统性肥大细胞增多症和急性髓性白血病中致癌性 KIT 发生混杂信号的细胞内机制尚不清楚。我们表明，SHP2 磷酸酶对于致癌性 KIT 诱导的体外生长和存活以及体内骨髓增生性疾病（MPD）是必不可少的。通过单独或与 PI3K 抑制剂联合使用新型 SHP2 抑制剂对 SHP2 进行基因破坏或治疗携带致癌基因的细胞，可以通过破坏涉及 p85α、SHP2 和 Gab2 的蛋白质复合物来纠正 MPD。重要的是，致癌性 KIT 位置 719 上的单个酪氨酸足以通过募集 p85α、SHP2 和 Gab2 复合物到致癌性 KIT 来引发 MPD。我们的结果表明，SHP2 磷酸酶是一种可用药的靶标，它与脂质激酶合作诱导 MPD。
