Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia
Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia
复制标题
DOI：
10.1182/blood-2003-11-3876
复制
发表时间：
2004-07-15
期刊：
影响因子：
20.3
通讯作者：
Biondi, A
中科院分区：
文献类型：
--
作者：
Tartaglia, M;Martinelli, S;Biondi, A
SHP-2是一种蛋白酪氨酸磷酸酶，在生长因子和细胞因子受体下游起信号转导作用。SHP-2在发育过程中是必需的，编码SHP-2的基因PTPN11的胚系突变会导致努南综合征。SHP-2在造血细胞发育中起着至关重要的作用。我们最近证实，体细胞PTPN11突变是幼年性粒-单核细胞白血病最常见的病变，在其他髓系恶性肿瘤的少部分儿童中也能观察到。在这里，我们报告PTPN11病变发生在儿童急性淋巴细胞白血病(ALL)。在317例B细胞前体ALL病例中有23例观察到突变，但在44例T系ALL儿童中未观察到突变。前者以CD19(+)/CD10(+)/cyIgM(-)免疫表型的TEL-AML1(-)患者多见。PTPN11、NRAS和KRAS2突变在很大程度上是相互排斥的，占常见ALL病例的三分之一。我们还发现，在69例儿童急性髓系白血病中，12例急性单核细胞白血病(FAB-M5)中有4例发生了PTPN11突变。白血病相关的PTPN11突变是错误的，并被预测会导致SHP-2功能增强。我们的发现为PTPN11病变在白血病发生中发挥更广泛的作用提供了证据，但也表明这些病变对克隆性扩张的贡献与谱系相关和分化阶段相关。(C)2004年，由美国血液病学会提供。
SHP-2 is a protein tyrosine phosphatase functioning as signal transducer downstream to growth factor and cytokine receptors. SHP-2 is required during development, and germline mutations in PTPN11, the gene encoding SHP-2, cause Noonan syndrome. SHP-2 plays a crucial role in hematopoietic cell development. We recently demonstrated that somatic PTPN11 mutations are the most frequent lesion in juvenile myelomonocytic leukemia and are observed in a smaller percentage of children with other myeloid malignancies. Here, we report that PTPN11 lesions occur in childhood acute lymphoblastic leukemia (ALL). Mutations were observed in 23 of 317 B-cell precursor ALL cases, but not among 44 children with T-lineage ALL. In the former, lesions prevalently occurred in TEL-AML1(-) cases with CD19(+)/CD10(+)/cyIgM(-) immunophenotype. PTPN11, NRAS, and KRAS2 mutations were largely mutually exclusive and accounted for one third of common ALL cases. We also show that, among 69 children with acute myeloid leukemia, PTPN11 mutations occurred in 4 of 12 cases with acute monocytic leukemia (FAB-M5). Leukemia-associated PTPN11 mutations were missense and were predicted to result in SHP-2 gain-of-function. Our findings provide evidence for a wider role of PTPN11 lesions in leukemogenesis, but also suggest a lineage-related and differentiation stage-related contribution of these lesions to clonal expansion. (C) 2004 by The American Society of Hematology.