LOSS OF THE NORMAL NF1 ALLELE FROM THE BONE-MARROW OF CHILDREN WITH TYPE-1 NEUROFIBROMATOSIS AND MALIGNANT MYELOID DISORDERS
LOSS OF THE NORMAL NF1 ALLELE FROM THE BONE-MARROW OF CHILDREN WITH TYPE-1 NEUROFIBROMATOSIS AND MALIGNANT MYELOID DISORDERS
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DOI：
10.1056/nejm199403033300903
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发表时间：
1994-03-03
影响因子：
158.5
通讯作者：
MCCORMICK, F
中科院分区：
文献类型：
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作者：
SHANNON, KM;OCONNELL, P;MCCORMICK, F
背景资料。患有1型神经纤维瘤病(NF-1)的儿童患恶性髓系疾病的风险增加。对核因子-1基因(NF1)的分析表明，在受影响的人中，其产物神经纤维蛋白的功能降低，NF1属于隐性癌症基因的肿瘤抑制类。这一模型与神经纤维蛋白加速RAS调节蛋白家族固有的鸟苷三磷酸水解性的证据是一致的。然而，在与核因子-1相关的良性肿瘤中还没有发现结构杂合性缺失的报道，而且只在少数恶性神经脊瘤和一些肿瘤衍生细胞系中检测到了这种杂合性缺失。方法：研究方法。我们研究了11例发生恶性髓系疾病的患有核因子-1的儿童的骨髓和父母的白细胞中提取的DNA。我们使用了NF1内部和附近的一系列多态标记来确定白血病的发生是否与基因的结构变化有关。结果。来自五名患者的骨髓样本显示杂合性丢失。在每种情况下，NF1等位基因都是从携带NF-1的父母那里继承而正常的等位基因被删除。结论。这些数据提供了证据，证明NF1可能作为肿瘤抑制等位基因在患有NF-1的儿童恶性髓系疾病中发挥作用，并且神经纤维蛋白是RAS在早期骨髓生成中的调节因子。
Background. Children with type 1 neurofibromatosis (NF-1) are at increased risk for malignant myeloid disorders. Analysis of the NF-1 gene (NF1) suggests that the function of its product, neurofibromin, is reduced in affected persons and that NF1 belongs to the tumor-suppressor class of recessive cancer genes. This model is consistent with evidence that neurofibromin accelerates the intrinsic guanosine triphosphate-hydrolyzing activity of the Ras family of regulatory proteins. Loss of constitutional heterozygosity has not been reported in the benign tumors associated with NF-1, however, and has only been detected in a few malignant neural-crest tumors and in some tumor-derived cell lines. Methods. We studied DNA extracted from the bone marrow of 11 children with NF-1 in whom malignant myeloid disorders developed and from parental leukocytes. We used a series of polymorphic markers within and near NF1 to determine whether leukemogenesis was associated with structural alterations of the gene. Results. Bone marrow samples from five patients showed loss of heterozygosity. In each case, the NF1 allele was inherited from a parent with NF-1 and the normal allele was deleted. Conclusions. These data provide evidence that NF1 may function as a tumor-suppressor allele in malignant myeloid diseases in children with NF-1 and that neurofibromin is a regulator of Ras in early myelopoiesis.