Bollag G, Clapp D W, Shih S, Adler F, Zhang Y Y, Thompson P, Lange B J, Freedman M H, McCormick F, Jacks T, Shannon K
Onyx Pharmaceuticals, Richmond, California 94806, USA.
Nat Genet. 1996 Feb;12(2):144-8. doi: 10.1038/ng0296-144.
Individuals with neurofibromatosis type 1 (NF1) are predisposed to certain cancers including juvenile chronic myelogenous leukaemia (JCML). The NF1 tumour-suppressor gene encodes a protein (neurofibromin) that accelerates GTP hydrolysis on Ras proteins. Here we show that primary leukaemic cells from children with NF1 show a selective decrease in NF1-like GTPase activating protein (GAP) activity for Ras but retain normal cellular GAP activity. Leukaemic cells also show an elevated percentage of Ras in the GTP-bound conformation. JCML cells are hypersensitive to granulocyte-macrophage colony stimulating factor (GM-CSF), and we observed a similar pattern of aberrant growth in haematopoietic cells from Nf1-/- mouse embryos. These data define a specific role for neurofibromin in negatively regulating GM-CSF signaling through Ras in haematopoietic cells and they suggest that hypersensitivity to GM-CSF may be a primary event in the development of JCML.
1型神经纤维瘤病（NF1）患者易患某些癌症，包括青少年慢性粒细胞白血病（JCML）。NF1肿瘤抑制基因编码一种蛋白质（神经纤维瘤蛋白），该蛋白可加速Ras蛋白上的GTP水解。我们在此表明，来自NF1患儿的原发性白血病细胞对Ras的NF1样GTP酶激活蛋白（GAP）活性有选择性降低，但保留正常的细胞GAP活性。白血病细胞还显示出处于GTP结合构象的Ras百分比升高。JCML细胞对粒细胞-巨噬细胞集落刺激因子（GM-CSF）高度敏感，并且我们在Nf1-/-小鼠胚胎的造血细胞中观察到了类似的异常生长模式。这些数据确定了神经纤维瘤蛋白在造血细胞中通过Ras负调节GM-CSF信号传导中的特定作用，并且表明对GM-CSF超敏可能是JCML发生发展中的一个主要事件。
