Nf1 deficiency causes Ras-mediated granulocyte macrophage colony stimulating factor hypersensitivity and chronic myeloid leukaemia
Nf1 deficiency causes Ras-mediated granulocyte macrophage colony stimulating factor hypersensitivity and chronic myeloid leukaemia
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DOI：
10.1038/ng0296-137
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发表时间：
1996-02-01
期刊：
影响因子：
30.8
通讯作者：
Copeland, NG
中科院分区：
文献类型：
--
作者：
Largaespada, DA;Brannan, CI;Copeland, NG
Ras信号转导通路在人髓性白血病中经常失调。例如，在一些青少年慢性髓细胞性白血病（JCML）患者中发现RAS基因的激活点突变，而其他JCML患者显示1型神经纤维瘤病（NF 1）基因（一种Ras GT3激活蛋白）的缺失。通过产生小鼠的造血系统重建与Nf 1缺陷的造血干细胞，我们表明，Nf 1基因的损失，本身就足以产生骨髓增生性症状与人类JCML。我们还提供了证据表明，Nf 1基因缺失诱导骨髓增生性疾病通过Ras介导的超敏反应粒细胞/巨噬细胞集落刺激因子（GM-CSF）。最后，我们描述了一种基因筛选，以确定在急性髓系白血病进展过程中与Nf 1基因丢失合作的基因。
The Ras signal transduction pathway is often deregulated in human myeloid leukaemia. For example, activating point mutations in RAS genes are found in some patients with juvenile chronic myelogenous leukaemia (JCML), while other patients with JCML show loss of the neurofibromatosis type 1 (NF1) gene, a Ras GTPase activating protein. By generating mice whose haematopoietic system is reconsituted with Nf1 deficient haematopoietic stem cells we show that Nf1 gene loss, by itself, is sufficient to produce the myeloproliferative symptoms associated with human JCML. We also provide evidence to indicate that Nf1 gene loss induces myeloproliferative disease through a Ras-mediated hypersensitivity to granulocyte/macrophage-colony stimulating factor (GM-CSF). Finally, we describe a genetic screen for identifying genes that cooperate with Nf1 gene loss during progression to acute myeloid leukaemia.