Homozygous inactivation of the NF1 gene in bone marrow cells from children with neurofibromatosis type 1 and malignant myeloid disorders
Homozygous inactivation of the NF1 gene in bone marrow cells from children with neurofibromatosis type 1 and malignant myeloid disorders
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DOI：
10.1056/nejm199706123362404
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发表时间：
1997-06-12
影响因子：
158.5
通讯作者：
Shannon, K
中科院分区：
文献类型：
--
作者：
Side, L;Taylor, B;Shannon, K
背景 患有 1 型神经纤维瘤病的幼儿患恶性骨髓疾病的风险是正常风险的 200 至 500 倍。 1 型神经纤维瘤病 (NF1) 基因编码神经纤维蛋白，这是一种对 Ras 蛋白转导的信号进行负调控的蛋白。遗传和生化数据支持这样的假设：NF1 在未成熟骨髓细胞中充当肿瘤抑制基因，但在 1 型神经纤维瘤病患者的白血病细胞中尚未证实 NF1 等位基因失活。方法使用体外转录和翻译系统，我们筛选了 18 名患有 1 型神经纤维瘤病和骨髓疾病的儿童的骨髓样本 导致蛋白质截短的 NF1 突变。在家族性神经纤维瘤病 1 型病例中，通过对患者及其受影响父母的基因组 DNA 进行直接测序来证实突变。结果 18 名儿童中有 9 名的样本含有异常肽片段，其中 8 名儿童的样本中发现了 NF1 基因的截短突变。八名儿童中的五名的骨髓样本中不存在正常的 NF1 等位基因。我们在每个患有 1 型家族性神经纤维瘤病的孩子的受影响父母的 DNA 中检测到相同的突变。结论 在一些 1 型神经纤维瘤病患者的白血病细胞中，NF1 基因的两个等位基因均失活。NF1 似乎在未成熟骨髓中发挥肿瘤抑制基因的作用。 (C) 1997 年，马萨诸塞州医学会。
Background The risk of malignant myeloid disorders in young children with neurofibromatosis type 1 is 200 to 500 times the normal risk. The gene for neurofibromatosis type 1 (NF1) encodes neurofibromin, a protein that negatively regulates signals transduced by Ras proteins. Genetic and biochemical data support the hypothesis that NF1 functions as a tumor-suppressor gene in immature myeloid cells, but inactivation of both NF1 alleles has not been demonstrated in leukemic cells from patients with neurofibromatosis type 1.Methods Using an in vitro transcription and translation system, we screened bone marrow samples from 18 children with neurofibromatosis type 1 and myeloid disorders for NF1 mutations that cause a truncated protein. Mutations were confirmed by direct sequencing of genomic DNA from the patients, and from their affected parents, in cases of familial neurofibromatosis type 1.Results Specimens from 9 of the 18 children contained abnormal peptide fragments, and truncating mutations of the NF1 gene were found in specimens from 8 of these children. The normal NF1 allele was absent in bone marrow samples from five of the eight children. We detected the same mutation in DNA from the affected parent of each child with familial neurofibromatosis type 1.Conclusions Both alleles of the NF1 gene are inactivated in leukemic cells in some patients with neurofibromatosis type 1. NF1 appears to function as a tumor-suppressor gene in immature myeloid. (C) 1997, Massachusetts Medical Society.