Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.
School of Informatics and Computing, Indiana University & Purdue University, Indianapolis, Indiana, USA.
JCI Insight. 2018 Feb 22;3(4). doi: 10.1172/jci.insight.94679.
Mutations in KIT and TET2 are associated with myeloid malignancies. We show that loss of TET2-induced PI3K activation and -increased proliferation is rescued by targeting the p110α/δ subunits of PI3K. RNA-Seq revealed a hyperactive c-Myc signature in Tet2-/- cells, which is normalized by inhibiting PI3K signaling. Loss of TET2 impairs the maturation of myeloid lineage-derived mast cells by dysregulating the expression of Mitf and Cebpa, which is restored by low-dose ascorbic acid and 5-azacytidine. Utilizing a mouse model in which the loss of TET2 precedes the expression of oncogenic Kit, similar to the human disease, results in the development of a non-mast cell lineage neoplasm (AHNMD), which is responsive to PI3K inhibition. Thus, therapeutic approaches involving hypomethylating agents, ascorbic acid, and isoform-specific PI3K inhibitors are likely to be useful for treating patients with TET2 and KIT mutations.
KIT 和 TET2 的突变与髓系恶性肿瘤有关。我们发现，通过靶向 PI3K 的 p110α/δ 亚基，可以挽救 TET2 诱导的 PI3K 激活和增殖增加。RNA-Seq 显示 Tet2-/- 细胞中存在过度活跃的 c-Myc 特征，通过抑制 PI3K 信号可以使其正常化。TET2 的缺失通过失调 Mitf 和 Cebpa 的表达来破坏髓系衍生的肥大细胞的成熟，而低剂量抗坏血酸和 5-氮杂胞苷可以恢复这种成熟。利用一种在其中 TET2 缺失先于致癌性 Kit 表达的小鼠模型，类似于人类疾病，导致非肥大细胞谱系肿瘤 (AHNMD) 的发展，该肿瘤对 PI3K 抑制有反应。因此，涉及低甲基化剂、抗坏血酸和同工型特异性 PI3K 抑制剂的治疗方法可能对治疗 TET2 和 KIT 突变的患者有用。
