Rapamycin inhibits growth and survival of D816V-mutated c-kit mast cells
Rapamycin inhibits growth and survival of D816V-mutated c-kit mast cells
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DOI：
10.1182/blood-2005-06-2433
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发表时间：
2006-08-01
期刊：
影响因子：
20.3
通讯作者：
Hermine, Olivier
中科院分区：
文献类型：
--
作者：
Gabillot-Carre, Marion;Lepelletier, Yves;Hermine, Olivier
c-kit酪氨酸激酶的两类致癌突变已被描述：近膜结构域V560G突变，优先发现于胃肠道间质瘤（gist）；激酶结构域D816V突变，高度代表系统性肥大细胞增多症（SM）。在这里，我们发现这两种突变都组成性地激活了雷帕霉素（mTOR）信号通路的哺乳动物靶点。令人惊讶的是，mTOR抑制剂雷帕霉素仅在携带D816V而不是V560G突变的hcc -1细胞中诱导细胞凋亡。为了支持这种意想不到的选择性，雷帕霉素抑制4E-BP1的磷酸化，mTOR途径的下游底物，但仅在D816V hcc -1细胞中。重要的是，从SM患者或转基因小鼠中分离的D816V肥大细胞对雷帕霉素敏感，而正常的人和小鼠肥大细胞则不敏感。因此，雷帕霉素的抑制作用似乎只针对D816V突变。目前对于携带D816V突变的SM患者还没有有效的治疗方法。本文提供的数据为检验雷帕霉素是否可能治疗SM和其他带有D816V突变的血液系统恶性肿瘤提供了理论依据。
Two classes of oncogenic mutations of the c-kit tyrosine kinase have been described: the juxtamembrane domain V560G mutation, which is preferentially found in gastrointestinal stromal tumors (GISTs), and the kinase domain D816V mutation, which is highly representative of systemic mastocytosis (SM). Here we show that both mutations constitutively activate the mammalian target of rapamycin (mTOR) signaling pathway. Surprisingly, the mTOR inhibitor rapamycin induces only apoptosis in HMC-1 cells bearing the D816V but not the V560G mutation. In support of this unexpected selectivity, rapamycin inhibits the phosphorylation of 4E-BP1, a downstream substrate of the mTOR pathway, but only in D816V HMC-1 cells. Importantly, D816V mast cells isolated from SM patients or from transgenic mice are sensitive to rapamycin whereas normal human or mouse mast cells are not. Thus, rapamycin inhibition appears specific to the D816V mutation. At present there is no effective cure for SM patients with the D816V mutation. The data presented here provide a rationale to test whether rapamycin could be a possible treatment for SM and other hematologic malignancies with the D816V mutation.