Role of phosphatidylinositol 3-kinase-Akt pathway in nucleophosmin/anaplastic lymphoma kinase-mediated lymphomagenesis.
Role of phosphatidylinositol 3-kinase-Akt pathway in nucleophosmin/anaplastic lymphoma kinase-mediated lymphomagenesis.
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发表时间：
2001-03
期刊：
影响因子：
11.2
通讯作者：
A. Słupianek;M. Nieborowska-Skorska;G. Hoser;A. Morrione;M. Majewski;L. Xue;S. Morris;M. Wasik;T. Skorski
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文献类型：
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作者：
A. Słupianek;M. Nieborowska-Skorska;G. Hoser;A. Morrione;M. Majewski;L. Xue;S. Morris;M. Wasik;T. Skorski
NPM/ALK融合基因由间变性大细胞淋巴瘤亚群中的t（2;5）易位形成，编码一种Mr 75，000杂合蛋白，该杂合蛋白含有核仁磷蛋白核磷蛋白（NPM）的NH 2末端部分，该部分与受体酪氨酸激酶间变性淋巴瘤激酶（ALK）的整个细胞质部分连接。NPM/ALK编码一种组成型激活的酪氨酸激酶，属于染色体易位激活的酪氨酸激酶家族。我们的研究表明，NPM/ALK，类似于该家族的其他成员，激活磷脂酰肌醇3-激酶（PI 3 K）及其下游效应物丝氨酸/苏氨酸激酶（Akt）。PI 3 K与NPM/ALK复合。PI 3 K和Akt激酶在NPM/ALK转染的BaF 3小鼠造血细胞和NPM/ALK阳性的患者源性间变性大细胞淋巴瘤细胞系中永久活化，但在NPM/ALK阴性的患者源性间变性大细胞淋巴瘤细胞系中未永久活化。此外，从4例诊断为ALK阳性T/空细胞淋巴瘤的患者中分离的蛋白质样本中，Akt被磷酸化/活化。PI 3 K抑制剂wortmannin和LY 294002诱导NPM/ALK+细胞凋亡，但对对照BaF 3亲本细胞和生长因子刺激的外周血单核细胞仅产生轻微影响。此外，逆转录病毒感染的NPM/ALK+ BaF 3细胞与显性负PI 3 K突变体（δ p85）或显性负Akt突变体（K179 M）抑制感染细胞的增殖和克隆形成特性。最后，Akt突变体（K179 M）抑制注射到同基因小鼠中的NPM/ALK转染的BaF 3细胞的致瘤性。总之，我们的数据表明，NPM/ALK组成型激活PI 3 K-Akt通路，该通路在NPM/ALK介导的恶性转化中起重要作用。
The NPM/ALK fusion gene, formed by the t(2;5) translocation in a subset of anaplastic large cell lymphomas, encodes a Mr 75,000 hybrid protein that contains the NH2-terminal portion of the nucleolar phosphoprotein nucleophosmin (NPM) joined to the entire cytoplasmic portion of the receptor tyrosine kinase anaplastic lymphoma kinase (ALK). NPM/ALK encodes a constitutively activated tyrosine kinase that belongs to the family of tyrosine kinases activated by chromosomal translocations. Our studies showed that NPM/ALK, similar to other members of this family, activates phosphatidylinositol 3-kinase (PI3K) and its downstream effector, serine/threonine kinase (Akt). PI3K was found in complex with NPM/ALK. Both PI3K and Akt kinase were permanently activated in NPM/ALK-transfected BaF3 murine hematopoietic cells and in NPM/ALK-positive, but not in NPM/ALK-negative, patient-derived anaplastic large cell lymphoma cell lines. In addition, Akt was phosphorylated/activated in protein samples isolated from four patients diagnosed with ALK-positive T/null-cell lymphomas. The PI3K inhibitors wortmannin and LY294002 induced apoptosis in NPM/ALK+ cells but exerted only minor effects on the control BaF3 parental cells and peripheral blood mononuclear cells stimulated by growth factors. Furthermore, retroviral infection of NPM/ALK+ BaF3 cells with a dominant-negative PI3K mutant (delta p85) or a dominant-negative Akt mutant (K179M) inhibited proliferation and clonogenic properties of the infected cells. Finally, the Akt mutant (K179M) suppressed the tumorigenicity of NPM/ALK-transfected BaF3 cells injected into syngeneic mice. In conclusion, our data indicate that NPM/ALK constitutively activates the PI3K-Akt pathway and that this pathway plays an important role in the NPM/ALK-mediated malignant transformation.