A critical role for Lyn in acute myeloid leukemia
A critical role for Lyn in acute myeloid leukemia
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DOI：
10.1182/blood-2007-04-082099
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发表时间：
2008-02-15
期刊：
影响因子：
20.3
通讯作者：
Recher, Christian
中科院分区：
文献类型：
--
作者：
Dos Santos, Ceric;Demur, Ceile;Recher, Christian
受体或非受体酪氨酸激酶(TKS)在白血病的发生中起重要作用。在这里，我们研究了一系列新鲜AML样本中蛋白质酪氨酸磷酸化的水平，并评估了TK抑制剂的效果。与正常造血祖细胞相比，大多数急性髓系白血病(AML)样本都检测到高水平的酪氨酸磷酸化。在大多数病例中，包括CD34(+)、CD38(-)、CD123(+)的酪氨酸磷酸化水平显示，Src家族的蛋白激酶(SFK)呈结构性激活。LYN是主要的SFK家族成员，在AML细胞中以活性形式表达，在AML细胞中异常分布于细胞膜和胞浆，而不是正常的造血祖细胞。SFK抑制剂PP2在不影响正常粒单核细胞集落形成单位的情况下，显著降低了酪氨酸磷酸化的整体水平，抑制了细胞增殖，并诱导了患者样本的凋亡。此外，通过小干扰RNA沉默原代AML细胞中Lyn的表达强烈抑制了细胞的增殖。有趣的是，观察到LYN和mTOR通路之间的联系，因为PP2和LYN基因敲除都影响mTOR靶标的磷酸化，而不抑制辅助：磷酸化。LYN有望成为治疗AML的新的药理靶点。
Receptor or nonreceptor tyrosine kinases (TKs) are known to play an important role in leukemogenesis. Here we studied the level of protein tyrosine phosphorylations in a series of fresh AML samples and evaluated the effect of TK inhibitors. Compared with normal hematopoietic progenitors, a high level of tyrosine phosphorylation was detected in most acute myeloid leukemia (AML) samples. The Src family kinases (SFKs) appeared constitutively activated in most cases, including in the CD34(+)CD38(-)CD123(+) compartment as revealed by the level of phosphorylated tyrosine 416. Lyn was the major SFK family member expressed in an active form in AML cells where it was abnormally distributed throughout the plasma membrane and the cytosol as opposed to normal hernatopoietic progenitors. The SFK inhibitor,PP2, strongly reduced the global level of tyrosine phosphorylations, inhibited cell proliferation, and induced apoptosis in patient samples without affecting normal granulomonocytic colony forming units. Moreover, silencing Lyn expression by small interfering RNA in primary AML cells strongly inhibited proliferation. Interestingly, a link between Lyn and the mTOR pathway was observed as PP2 and a Lyn knockdown both affected the phosphorylation of mTOR targets without inhibiting Aid: phosphorylation. Lyn should be considered as a novel pharmacologic target for AML therapy.