Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN.
Leukemia. 2012 Jul;26(7):1499-1506. doi: 10.1038/leu.2012.22. Epub 2012 Feb 2.
Gain-of-function mutations in KIT receptor in humans are associated with gastrointestinal stromal tumors, systemic mastocytosis and acute myelogenous leukemia. The intracellular signals that contribute to oncogenic KIT-induced myeloproliferative disease (MPD) are poorly understood. Here, we show that oncogenic KITD814V-induced MPD occurs in the absence of ligand stimulation. The intracellular tyrosine residues are important for KITD814V-induced MPD, albeit to varying degrees. Among the seven intracellular tyrosines examined, tyrosine 719 alone has a unique role in regulating KITD814V-induced proliferation and survival in vitro, and MPD in vivo. Importantly, the extent to which AKT, extracellular signal-regulated kinase and Stat5 signaling pathways are activated via the seven intracellular tyrosines in KITD814V impacts the latency of MPD and severity of the disease. Our results identify critical signaling molecules involved in regulating KITD814V-induced MPD, which might be useful for developing novel therapeutic targets for hematologic malignancies involving this mutation.
人类 KIT 受体的功能获得性突变与胃肠道间质肿瘤、全身性肥大细胞增多症和急性髓性白血病有关。导致致癌性 KIT 诱导的骨髓增生性疾病（MPD）的细胞内信号仍知之甚少。在这里，我们表明，在没有配体刺激的情况下，致癌性 KITD814V 诱导的 MPD 发生。细胞内的酪氨酸残基对于 KITD814V 诱导的 MPD 很重要，尽管程度不同。在研究的七个细胞内酪氨酸中，只有酪氨酸 719 在体外调节 KITD814V 诱导的增殖和存活以及体内 MPD 方面具有独特的作用。重要的是，通过 KITD814V 中的七个细胞内酪氨酸激活的 AKT、细胞外信号调节激酶和 Stat5 信号通路的程度会影响 MPD 的潜伏期和疾病的严重程度。我们的研究结果确定了参与调节 KITD814V 诱导的 MPD 的关键信号分子，这可能有助于开发涉及这种突变的血液恶性肿瘤的新型治疗靶点。
