Balgobind Brian V, Van Vlierberghe Pieter, van den Ouweland Ans M W, Beverloo H Berna, Terlouw-Kromosoeto Joan N R, van Wering Elisabeth R, Reinhardt Dirk, Horstmann Martin, Kaspers Gertjan J L, Pieters Rob, Zwaan C Michel, Van den Heuvel-Eibrink Marry M, Meijerink Jules P P
Department of Pediatric Oncology/Hematology, Erasmus MC / Sophia Children's Hospital, Rotterdam, The Netherlands.
Blood. 2008 Apr 15;111(8):4322-8. doi: 10.1182/blood-2007-06-095075. Epub 2008 Jan 2.
Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder caused by mutations in the NF1 gene. Patients with NF1 have a higher risk to develop juvenile myelomonocytic leukemia (JMML) with a possible progression toward acute myeloid leukemia (AML). In an oligo array comparative genomic hybridization-based screening of 103 patients with pediatric T-cell acute lymphoblastic leukemia (T-ALL) and 71 patients with MLL-rearranged AML, a recurrent cryptic deletion, del(17)(q11.2), was identified in 3 patients with T-ALL and 2 patients with MLL-rearranged AML. This deletion has previously been described as a microdeletion of the NF1 region in patients with NF1. However, our patients lacked clinical NF1 symptoms. Mutation analysis in 4 of these del(17)(q11.2)-positive patients revealed that mutations in the remaining NF1 allele were present in 3 patients, confirming its role as a tumor-suppressor gene in cancer. In addition, NF1 inactivation was confirmed at the RNA expression level in 3 patients tested. Since the NF1 protein is a negative regulator of the RAS pathway (RAS-GTPase activating protein), homozygous NF1 inactivation represent a novel type I mutation in pediatric MLL-rearranged AML and T-ALL with a predicted frequency that is less than 10%. NF1 inactivation may provide an additional proliferative signal toward the development of leukemia.
1型神经纤维瘤病（NF1）是一种由NF1基因突变引起的常染色体显性遗传病。NF1患者发生青少年粒单核细胞白血病（JMML）并可能进展为急性髓系白血病（AML）的风险更高。在一项基于寡核苷酸阵列比较基因组杂交的筛查中，对103例儿童T细胞急性淋巴细胞白血病（T-ALL）患者和71例MLL重排的AML患者进行检测，在3例T-ALL患者和2例MLL重排的AML患者中发现了复发性隐匿性缺失del(17)(q11.2)。这种缺失先前已被描述为NF1患者中NF1区域的微缺失。然而，我们的患者缺乏NF1的临床症状。对4例del(17)(q11.2)阳性患者进行的突变分析显示，3例患者的其余NF1等位基因存在突变，证实了其在癌症中作为肿瘤抑制基因的作用。此外，在3例接受检测的患者中，在RNA表达水平上证实了NF1失活。由于NF1蛋白是RAS途径的负调节因子（RAS-鸟苷三磷酸酶激活蛋白），纯合性NF1失活代表了小儿MLL重排的AML和T-ALL中的一种新型I型突变，预测频率小于10%。NF1失活可能为白血病的发展提供额外的增殖信号。
