Alteration of phosphatidylinositol 3-kinase cascade in the multilobulated nuclear formation of adult T cell leukemia/lymphoma (ATLL)
Alteration of phosphatidylinositol 3-kinase cascade in the multilobulated nuclear formation of adult T cell leukemia/lymphoma (ATLL)
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DOI：
10.1073/pnas.0507184102
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发表时间：
2005-10-18
影响因子：
11.1
通讯作者：
Tsuji, T
中科院分区：
文献类型：
--
作者：
Fukuda, R;Hayashi, A;Tsuji, T
成人T细胞白血病/淋巴瘤（ATLL）已被表征为最具侵袭性的人类肿瘤之一，并且其发病率被认为是由感染人T细胞白血病病毒I型（HTLV-I）的T细胞的宿主细胞基因的遗传和表观遗传改变引起的。多小叶核外观是ATLL的重要诊断标志物，我们现在已经确定，这些形成的分子机制是通过AILIM/ICOS信号转导激活磷脂酰肌醇3-激酶（PI 3-激酶），通过微管重排发生的。我们还表明，PTEN和/或SHIP-1，这是PIP 3肌醇磷酸酶，抑制PI 3激酶级联的下游效应物的激活，在ATLL肿瘤和多小叶核形成Jurkat细胞中被破坏。这种下调的PTEN被认为是必不可少的ATLL型核小叶的形成。此外，观察到PI 3-激酶和PTEN活性与细胞增殖密切相关。因此，我们的研究结果表明，PI 3-激酶信号级联的改变，作为肌醇磷酸酶的下调的结果，诱导ATLL型多小叶核形成，也与恶性T细胞白血病/淋巴瘤的细胞增殖。
Adult T cell leukemia/lymphoma (ATLL) has been characterized as one of the most aggressive human neoplasias and its incidence is thought to be caused by both genetic and epigenetic alterations to the host cellular genes of T cells infected with human T cell leukemia virus type I (HTLV-I). A multilobulated nuclear appearance is an important diagnostic marker of ATLL, and we have now identified that the molecular mechanisms underlying these formations occur through microtubule rearrangement via phosphaticlylinositol 3-kinase (PI3-kinase) activation by AILIM/ICOS signaling. We also show that PTEN and/or SHIP-1, which are PIP3 inositol phosphatases that inhibit the activation of downstream effectors of the PI3-kinase cascade, are disrupted in both ATLL neoplasias and in multilobulated nuclei-forming Jurkat cells. This downregulation of PTEN was found to be essential for the formation of ATLL-type nuclear lobules. Furthermore, PI3-kinase and PTEN activities were observed to be closely associated with cellular proliferation. Thus, our results suggest that alteration of PI3-kinase signaling cascades, as a result of the down-regulation of inositol phosphatases, induces ATLL-type multilobulated nuclear formation and is also associated with the cellular proliferation of malignant T cell leukemias/lymphomas.