Pim-1 is up-regulated by constitutively activated FLT3 and plays a role in FLT3-mediated cell survival
Pim-1 is up-regulated by constitutively activated FLT3 and plays a role in FLT3-mediated cell survival
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DOI：
10.1182/blood-2004-05-2006
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发表时间：
2005-02-15
期刊：
影响因子：
20.3
通讯作者：
Small, D
中科院分区：
文献类型：
--
作者：
Kim, KT;Baird, K;Small, D
受体酪氨酸激酶FLT 3（Fms样酪氨酸激酶3）的组成性激活内部串联重复（ITD）突变在白血病发生中起重要作用，并且它们的存在与急性髓性白血病（AML）的不良预后相关。为了更好地理解FLT 3信号在白血病发生中的作用，我们研究了FLT 3/ITD或组成型激活的野生型FLT 3表达诱导的基因表达变化。微阵列与在抑制FLT 3信号传导之前和之后收获的RNA一起使用。发现Pim-1是FLT 3抑制后最显著下调的基因之一。Pim-1是一种原癌基因，已知可被信号转导和转录激活因子5（STAT 5）上调，而STAT 5本身是FLT 3信号转导的下游靶点。定量聚合酶链反应（QPCR）证实了微阵列结果，并证明响应于FLT 3抑制，Pim-1表达减少了约10倍。Pim-1蛋白也随着FLT 3自身磷酸化活性的降低而迅速降低。44-kDa或33-kDa Pim-1同种型的强制表达导致对FLT 3抑制介导的细胞毒性和细胞凋亡的抗性增加。相比之下，显性阴性Pim-1构建体的表达加速了响应于FLT 3抑制的细胞毒性，并抑制了FLT 3/ITD转化的BaF 3细胞的集落生长。这些发现表明，组成性激活的FLT 3信号上调白血病细胞中的Pim-1表达。这种上调有助于FLT 3信号传导诱导的增殖和抗凋亡途径。(C)2005年，美国血液学会。
Constitutively activating internal tandem duplication (ITD) mutations of the receptor tyrosine kinase FLT3 (Fms-like tyrosine kinase 3) play an important role in leukemogenesis, and their presence is associated with poor prognosis in acute myeloid leukemia (AML). To better understand FLT3 signaling in leukemogenesis, we have examined the changes in gene expression induced by FLT3/ITD or constitutively activated wild-type FLT3 expression. Microarrays were used with RNA harvested before and after inhibition of FLT3 signaling. Pim-1 was found to be one of the most significantly down-regulated genes upon FLT3 inhibition. Pim-1 is a proto-oncogene and is known to be up-regulated by signal transducer and activator of transcription 5 (STAT5), which itself is a downstream target of FLT3 signaling. Quantitative polymerase chain reaction (QPCR) confirmed the microarray results and demonstrated approximately 10-fold decreases in Pim-1 expression in response to FLT3 inhibition. Pim-1 protein also decreased rapidly in parallel with decreasing autophosphorylation activity of FLT3. Enforced expression of either the 44-kDa or 33-kDa Pim-1 isotypes resulted in increased resistance to FLT3 inhibition-mediated cytotoxicity and apoptosis. In contrast, expression of a dominant-negative Pim-1 construct accelerated cytotoxicity in response to FLT3 inhibition and inhibited colony growth of FLT3/ITD-transformed BaF3 cells. These findings demonstrate that constitutively activated FLT3 signaling up-regulates Pim-1 expression in leukemia cells. This up-regulation contributes to the proliferative and antiapoptotic pathways induced by FLT3 signaling. (C) 2005 by The American Society of Hematology.