Direct activation of STAT5 by ETV6-LYN fusion protein promotes induction of myeloproliferative neoplasm with myelofibrosis.
Direct activation of STAT5 by ETV6-LYN fusion protein promotes induction of myeloproliferative neoplasm with myelofibrosis.
复制标题
DOI：
10.1111/j.1365-2141.2011.08663.x
复制
发表时间：
2011-06
影响因子：
6.5
通讯作者：
Iwama A
中科院分区：
文献类型：
--
作者：
Takeda Y;Nakaseko C;Tanaka H;Takeuchi M;Yui M;Saraya A;Miyagi S;Wang C;Tanaka S;Ohwada C;Sakaida E;Yamaguchi N;Yokote K;Hennighausen L;Iwama A
骨髓增生性肿瘤（MPN）是一组造血干细胞（HSC）疾病，通常伴有骨髓纤维化。我们先前在伴有ins（12;8）（p13; q11 q21）的特发性骨髓纤维化中鉴定了ETV 6基因与林恩基因的融合（ETV 6-林恩）。将ETV 6-林恩引入HSC导致小鼠中具有大量骨髓纤维化的致命性MPN，这暗示重排的林恩激酶在具有骨髓纤维化的MPN的发病机制中。然而，直接位于ETV 6-林恩下游并被其激活的信号分子仍然未知。在这项研究中，我们证明了ETV 6-林恩直接激活STAT 5对MPN的发展至关重要。ETV 6-林恩通过自磷酸化具有组成型激酶活性。ETV 6-林恩，而不是其激酶死亡突变体，支持造血细胞的无精氨酸增殖。STAT 5在ETV 6-LYN表达细胞中以JAK 2非依赖性方式被激活。ETV 6-林恩与STAT 5相互作用并在体外和体内直接激活STAT 5。值得注意的是，ETV 6-林恩不支持Stat 5缺陷型HSC在无精氨酸条件下形成集落，并且ETV 6-林恩诱导MPN伴骨髓纤维化的能力在Stat 5缺失背景下显著减弱。这些发现将STAT 5定义为ETV 6-林恩的直接靶点，并揭示了LYN-STAT 5轴作为增强MPN和白血病增殖信号的新途径。
Myeloproliferative neoplasms (MPN), a group of haematopoietic stem cell (HSC) disorders, are often accompanied by myelofibrosis. We previously identified the fusion of the ETV6 gene to the LYN gene (ETV6-LYN) in idiopathic myelofibrosis with ins(12;8)(p13;q11q21). The introduction of ETV6-LYN into HSCs resulted in fatal MPN with massive myelofibrosis in mice, implicating the rearranged LYN kinase in the pathogenesis of MPN with myelofibrosis. However, the signalling molecules directly downstream from and activated by ETV6-LYN remain unknown. In this study, we demonstrated that the direct activation of STAT5 by ETV6-LYN is crucial for the development of MPN. ETV6-LYN was constitutively active as a kinase through autophosphorylation. ETV6-LYN, but not its kinase-dead mutant, supported cytokine-free proliferation of haematopoietic cells. STAT5 was activated in a JAK2-independent manner in ETV6-LYN-expressing cells. ETV6-LYN interacted with STAT5 and directly activated STAT5 both in vitro and in vivo. Of note, ETV6-LYN did not support the formation of colonies by Stat5-deficient HSCs under cytokine-free conditions and the capacity of ETV6-LYN to induce MPN with myelofibrosis was profoundly attenuated in a Stat5-null background. These findings define STAT5 as a direct target of ETV6-LYN and unveil the LYN-STAT5 axis as a novel pathway to augment proliferative signals in MPN and leukaemia.
登录
查看更多内容
影响因子：
15.8
作者：
Pikman, Yana;Lee, Benjamin H.;Mercher, Thomas;McDowell, Elizabeth;Ebert, Benjamin L.;Gozo, Maricel;Cuker, Adam;Wernig, Gerlinde;Moore, Sandra;Galinsky, Ilene;DeAngelo, Daniel J.;Clark, Jennifer J.;Lee, Stephanie J.;Golub, Todd R.;Wadleigh, Martha;Gilliland, D. Gary;Levine, Ross L.
通讯作者：
Levine, Ross L.
影响因子：
2.6
作者：
Liu, Geqiang;Wang, Zhengqi;Bunting, Kevin D.
通讯作者：
Bunting, Kevin D.
影响因子：
4.8
作者：
Schreiner, SJ;Schiavone, AP;Smithgall, TE
通讯作者：
Smithgall, TE
影响因子：
4.4
作者：
Dai, Xuezhi;Chen, Yuhong;Wang, Demin
通讯作者：
Wang, Demin
影响因子：
6.5
作者：
MARTYRE, MC;ROMQUIN, N;BAUTERS, F
通讯作者：
BAUTERS, F