Garicochea B, Giorgi R, Odone V F, Dorlhiac-Llacer P E, Bendit I
Fundação Pró-Sangue Hemocentro de São Paulo Hematology/Hemotherapy Department, Hospital das Clínicas, Brazil.
Leuk Res. 1998 Nov;22(11):1003-7. doi: 10.1016/s0145-2126(98)00076-9.
RAS mutations can be detected in a variable number of patients with myeloproliferative disorders such as myelodysplastic syndromes and acute myeloid leukemia, but are rare events in chronic myelogenous leukemia in chronic phase. However, there is good evidence supporting the involvement of RAS signalling pathway in CML and this could be due to alterations in RAS activity regulatory proteins. The neurofibromatosis (NF1) gene down-regulates the RAS signal transduction pathway through the inhibitory function of its GAP-related domain (GRD) on RAS protein. The loss or alteration of neurofibromin (the NF1 protein) may produce a disfunction similar to point mutations in the RAS gene resulting in the permanent stimulation of the RAS signal transduction pathway. Mutations involving the GRD region of the NF1 gene (GRD-NF1) have been described in a variety of tumors such as colon carcinoma and astrocytoma. Germline mutations and deletions in the NF1 gene, as seen in neurofibromatosis type 1, are also associated with certain myeloid disorders. In the present work, we sought to identify mutations in the codons 12/13 and 61 of RAS gene and in the Lys-1423 codon of GRD-NF1, which are well known hot spots in these genes, in a group of 36 adults and ten children with chronic myelogenous leukemia in chronic phase and blast crisis. Using the PCR-SSCP and the allele-specific restriction assay (ASRA) techniques, we were not able to observe any RAS or NF1 detectable mutation. These findings suggest that RAS and GRD-NF1 mutations are not involved either in chronic phase or in the progression to blast crisis in chronic myelogenous leukemia in adults and children.
在许多患有骨髓增生异常综合征和急性髓系白血病等骨髓增殖性疾病的患者中可检测到RAS突变，但在慢性期慢性髓性白血病中却是罕见事件。然而，有充分证据支持RAS信号通路参与慢性髓性白血病，这可能是由于RAS活性调节蛋白的改变所致。神经纤维瘤病（NF1）基因通过其GAP相关结构域（GRD）对RAS蛋白的抑制功能来下调RAS信号转导通路。神经纤维瘤蛋白（NF1蛋白）的缺失或改变可能产生类似于RAS基因点突变的功能障碍，导致RAS信号转导通路的持续激活。涉及NF1基因GRD区域（GRD-NF1）的突变已在多种肿瘤如结肠癌和星形细胞瘤中被描述。如1型神经纤维瘤病中所见的NF1基因种系突变和缺失也与某些髓系疾病相关。在本研究中，我们试图在36名成人和10名儿童慢性期和急变期慢性髓性白血病患者中鉴定RAS基因密码子12/13和61以及GRD-NF1的赖氨酸-1423密码子中的突变，这些是这些基因中众所周知的热点区域。使用PCR-SSCP和等位基因特异性限制性分析（ASRA）技术，我们未能观察到任何可检测到的RAS或NF1突变。这些发现表明，RAS和GRD-NF1突变在成人和儿童慢性髓性白血病的慢性期或进展为急变期过程中均未发挥作用。
