BCR gene expression blocks Bcr-Abl induced pathogenicity in a mouse model
BCR gene expression blocks Bcr-Abl induced pathogenicity in a mouse model
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DOI：
10.1038/sj.onc.1204409
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发表时间：
2001-04-05
期刊：
影响因子：
8
通讯作者：
Arlinghaus, RB
中科院分区：
文献类型：
--
作者：
Lin, F;Monaco, G;Arlinghaus, RB
人们普遍认为，费城染色体编码的 Bcr-Abl 癌蛋白负责引起慢性粒细胞性白血病 (CML)。我们之前已经证明，Bcr 的表达会干扰 Bcr-Abl 的致癌作用。为了在更生理的系统中检查 Bcr 表达增加对 Bcr-Abl 致癌作用的影响，我们测试了含有诱导蛋白的 K562 细胞克隆 (K6 K562) 的致白血病潜力。 NOD/scid 小鼠中的 BCR 基因。在此克隆中，BCR 基因置于带有巨细胞病毒 (CMV) 启动子的四环素 (Tet) 抑制系统的控制下。通过从培养基中去除Tet来诱导外源Bcr蛋白导致Bcr丝氨酸激酶活性显着增加，尽管激酶反应混合物中存在Bcr-Abl，但主要产生磷酸丝氨酸Bcr。在诱导之前，由于 Bcr-Abl 的磷酸化，内源性 Bcr 主要呈磷酸酪氨酸形式，我们之前已证明 Bcr-Abl 会抑制 Bcr 丝氨酸/苏氨酸激酶活性。在 BCR 表达受到抑制的条件下，将 K6 K562 细胞注射到 NOD/scid 小鼠中，导致注射后 35 天内 100% 的小鼠死亡或绝症。这些小鼠患有严重消耗综合征，其特征是骨髓造血萎缩和/或肝脏、骨髓和脾脏肿瘤。这些小鼠的肿瘤性脾脏通常含有 b3a2 Bcr-Abl 转录本。相比之下，注射时诱导 BCR 表达可实现 80% 的存活率；这些健康小鼠的造血器官中没有可检测到的微观损伤。这种生存差异在 P 组中显着
It is well accepted that the Bcr-Abl oncoprotein encoded by the Philadelphia chromosome is responsible for causing chronic myelogenous leukemia (CML), We have previously demonstrated that expression of Bcr interferes with the oncogenic effects of Bcr-Abl, To examine the effects of increased Bcr expression on Bcr-Abl oncogenic effects in a more physiological system, we tested the leukemogenic potential of a clone of K562 cells (K6 K562) containing an inducible BCR gene in NOD/scid mice. In this clone, the BCR gene was placed under the control of a tetracycline (Tet) repression system with a cytomegalovirus (CMV) promoter. Induction of exogenous Bcr protein by removal of Tet from the culture medium caused a dramatic increase in Bcr serine kinase activity, yielding predominantly phosphoserine Bcr, despite the presence of Bcr-Abl in the kinase reaction mixture. Prior to induction, the endogenous Bcr was predominantly in the phosphotyrosine form because of phosphorylation by Bcr-Abl, which we previously have shown suppresses Bcr serine/threonine kinase activity, Injection of K6 K562 cells into NOD/scid mice under conditions where BCR expression was suppressed resulted in death or terminal illness in 100% of the mice within 35 days after injection. These mice had a severe wasting syndrome characterized by atrophy of bone marrow hematopoiesis, and/or neoplasia of liver, bone marrow and spleen. Neoplastic spleens from these mice usually contained b3a2 Bcr-Abl transcripts. In contrast, induction of BCR expression at the time of injection allowed 80% survival; these healthy mice had no detectable microscopic lesions in blood forming organs. This difference in survival was significant with P