Role of Dok-1 and Dok-2 in myeloid homeostasis and suppression of leukemia.
Role of Dok-1 and Dok-2 in myeloid homeostasis and suppression of leukemia.
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DOI：
10.1084/jem.20041247
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发表时间：
2004-12-20
期刊：
影响因子：
--
通讯作者：
Yamanashi Y
中科院分区：
文献类型：
--
作者：
Yasuda T;Shirakata M;Iwama A;Ishii A;Ebihara Y;Osawa M;Honda K;Shinohara H;Sudo K;Tsuji K;Nakauchi H;Iwakura Y;Hirai H;Oda H;Yamamoto T;Yamanashi Y
Dok-1和Dok-2是密切相关的rasGAP相关对接蛋白，优先在造血细胞中表达。尽管它们在许多蛋白酪氨酸激酶（PTK）（包括与细胞因子受体和致癌PTK（如Bcr-Abl）偶联的那些蛋白酪氨酸激酶）活化后被磷酸化，但它们的生理作用在很大程度上未被鉴定。在这里，我们产生了缺乏Dok-1和/或Dok-2的小鼠，其中包括死于类似于人类慢性粒细胞白血病（CML）和慢性粒单核细胞白血病的骨髓增生性疾病的双缺陷小鼠。双缺陷小鼠表现出髓内和髓外具有白血病潜能的粒细胞/巨噬细胞祖细胞增生，并且它们的髓样细胞分别在处理和剥夺细胞因子后表现出过度增殖和低凋亡。一致地，突变骨髓细胞在细胞因子刺激后显示增强的Erk和Akt活化。此外，Dok-1和/或Dok-2的缺失诱导携带bcr-abl基因的小鼠发生慢性期CML样疾病的急变，这是CML的一个病因。这些发现表明，Dok-1和Dok-2是细胞因子应答的关键负调节因子，并且对于骨髓稳态和抑制白血病是必需的。
Dok-1 and Dok-2 are closely related rasGAP-associated docking proteins expressed preferentially in hematopoietic cells. Although they are phosphorylated upon activation of many protein tyrosine kinases (PTKs), including those coupled with cytokine receptors and oncogenic PTKs like Bcr-Abl, their physiological roles are largely unidentified. Here, we generated mice lacking Dok-1 and/or Dok-2, which included the double-deficient mice succumbed to myeloproliferative disease resembling human chronic myelogenous leukemia (CML) and chronic myelomonocytic leukemia. The double-deficient mice displayed medullary and extramedullary hyperplasia of granulocyte/macrophage progenitors with leukemic potential, and their myeloid cells showed hyperproliferation and hypo-apoptosis upon treatment and deprivation of cytokines, respectively. Consistently, the mutant myeloid cells showed enhanced Erk and Akt activation upon cytokine stimulation. Moreover, loss of Dok-1 and/or Dok-2 induced blastic transformation of chronic phase CML-like disease in mice carrying the bcr-abl gene, a cause of CML. These findings demonstrate that Dok-1 and Dok-2 are key negative regulators of cytokine responses and are essential for myeloid homeostasis and suppression of leukemia.
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影响因子：
20.3
作者：
Honda, H;Ushijima, T;Hirai, H
通讯作者：
Hirai, H
影响因子：
20.3
作者：
Honda, H;Oda, H;Hirai, H
通讯作者：
Hirai, H
影响因子：
64.5
作者：
Yamanashi, Y;Baltimore, D
通讯作者：
Baltimore, D
影响因子：
4.8
作者：
Berg, KL;Siminovitch, KA;Stanley, ER
通讯作者：
Stanley, ER
DOI：
10.1083/jcb.200112066
发表时间：
2002-07-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gugasyan R;Quilici C;I ST;Grail D;Verhagen AM;Roberts A;Kitamura T;Dunn AR;Lock P
通讯作者：
Lock P