Ma Z, Cools J, Marynen P, Cui X, Siebert R, Gesk S, Schlegelberger B, Peeters B, De Wolf-Peeters C, Wlodarska I, Morris S W
Department of Pathology and Laboratory Medicine, St. Jude Children's Research Hospital, University of Tennessee, College of Medicine, Memphis, TN 38105-2794, USA.
Blood. 2000 Mar 15;95(6):2144-9.
The non-Hodgkin lymphoma (NHL) subtype anaplastic large-cell lymphoma (ALCL) is frequently associated with a t(2;5)(p23;q35) that results in the fusion of the ubiquitously expressed nucleophosmin (NPM) gene at 5q35 to the anaplastic lymphoma kinase (ALK) gene at 2p23, which is not normally expressed in hematopoietic tissues. Approximately 20% of ALCLs that express ALK do not contain the t(2;5), suggesting that other genetic abnormalities can result in aberrant ALK expression. Here we report the molecular characterization of an alternative genetic means of ALK activation, the inv(2)(p23q35). This recurrent abnormality produces a fusion of the amino-terminus of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), a bifunctional homodimeric enzyme that catalyzes the penultimate and final steps of de novo purine nucleotide biosynthesis, with the intracellular portion of the ALK receptor tyrosine kinase. RT-PCR analysis of 5 ALCL tumors that contained the inv(2) revealed identical ATIC-ALK fusion cDNA junctions in all of the cases. Transient expression studies show that the ATIC-ALK fusion transcript directs the synthesis of an approximately 87-kd chimeric protein that is localized to the cytoplasm, in contrast to NPM-ALK, which typically exhibits a cytoplasmic and nuclear subcellular distribution. ATIC-ALK was constitutively tyrosine phosphorylated and could convert the IL-3-dependent murine hematopoietic cell line BaF3 to cytokine-independent growth. Our studies demonstrate an alternative mechanism for ALK involvement in the genesis of NHL and suggest that ATIC-ALK activation results from ATIC-mediated homodimerization. In addition, expected decreases in ATIC enzymatic function in ATIC-ALK-containing lymphomas may render these tumors more sensitive to antifolate drugs such as methotrexate. (Blood. 2000;95:2144-2149)
非霍奇金淋巴瘤（NHL）亚型间变性大细胞淋巴瘤（ALCL）常与t(2;5)(p23;q35)相关，该异常导致位于5q35的普遍表达的核磷蛋白（NPM）基因与位于2p23的间变性淋巴瘤激酶（ALK）基因融合，而ALK基因在造血组织中通常不表达。约20%表达ALK的ALCL不含有t(2;5)，这表明其他基因异常可导致ALK异常表达。在此，我们报告了ALK激活的另一种遗传方式——inv(2)(p23q35)的分子特征。这种反复出现的异常导致5-氨基咪唑-4-甲酰胺核糖核苷酸甲酰基转移酶/IMP环水解酶（ATIC）（一种催化嘌呤核苷酸从头生物合成倒数第二步和最后一步的双功能同型二聚体酶）的氨基末端与ALK受体酪氨酸激酶的细胞内部分融合。对5例含有inv(2)的ALCL肿瘤进行逆转录聚合酶链反应（RT-PCR）分析，结果显示所有病例中ATIC-ALK融合cDNA连接均相同。瞬时表达研究表明，与通常表现为细胞质和细胞核亚细胞分布的NPM-ALK不同，ATIC-ALK融合转录本指导合成一种约87-kd的嵌合蛋白，该蛋白定位于细胞质。ATIC-ALK持续酪氨酸磷酸化，并可使依赖白细胞介素-3的小鼠造血细胞系BaF3转变为不依赖细胞因子生长。我们的研究证明了ALK参与NHL发生的另一种机制，并提示ATIC-ALK激活是由ATIC介导的同型二聚化导致的。此外，含有ATIC-ALK的淋巴瘤中ATIC酶功能预期的降低可能使这些肿瘤对甲氨蝶呤等抗叶酸药物更敏感。（《血液》。2000年；95:2144 - 2149）
