Bcr-Abl efficiently induces a myeloproliferative disease and production of excess interleukin-3 and granulocyte-macrophage colony-stimulating factor in mice: a novel model for chronic myelogenous leukemia.
Bcr-Abl efficiently induces a myeloproliferative disease and production of excess interleukin-3 and granulocyte-macrophage colony-stimulating factor in mice: a novel model for chronic myelogenous leukemia.
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DOI：
10.1182/blood.v92.10.3829.422k14_3829_3840
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发表时间：
1998-11
期刊：
影响因子：
20.3
通讯作者：
Xiaowu Zhang;R. Ren
中科院分区：
文献类型：
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作者：
Xiaowu Zhang;R. Ren
bcr-abl癌基因在引起慢性粒细胞白血病（CML）中起关键作用。需要有效的CML实验动物模型来研究bcr-abl癌基因在CML疾病进展中作用的分子机制。我们使用鼠干细胞逆转录病毒载体（MSCV）将bcr-abl/p210癌基因转染到小鼠骨髓细胞中，发现Bcr-Abl/p210的表达在约3周内诱导了100%骨髓移植小鼠出现类似于人类CML慢性期的骨髓增生性疾病。这种CML样疾病很容易移植到第二受体小鼠。感染细胞的多个克隆在第一受体中扩增，但白血病在第二受体小鼠中主要是单克隆的。突变分析表明Bcr-Abl/p210的蛋白酪氨酸激酶活性是其体内致白血病潜能所必需的。有趣的是，我们发现白血病细胞表达过量的白细胞介素-3（IL-3）和粒细胞-巨噬细胞集落刺激因子（GM-CSF）。这些研究表明，Bcr-Abl的表达可以在小鼠中诱导CML样白血病，比以前报道的小鼠CML模型更有效和可重复，可能是由于在正确的靶细胞中的有效表达。我们首次使用该模型分析CML相关的分子机制，提出了IL-3和GM-CSF等造血生长因子的过度表达可能导致CML临床表型的可能性。
The bcr-abl oncogene plays a critical role in causing chronic myelogenous leukemia (CML). Effective laboratory animal models of CML are needed to study the molecular mechanisms by which the bcr-abl oncogene acts in the disease progression of CML. We used a murine stem cell retroviral vector (MSCV) to transduce the bcr-abl/p210 oncogene into mouse bone marrow cells and found that expression of Bcr-Abl/p210 induced a myeloproliferative disorder that resembled the chronic phase of human CML in 100% of bone marrow transplanted mice in about 3 weeks. This CML-like disease was readily transplanted to secondary recipient mice. Multiple clones of infected cells were expanded in the primary recipients, but the leukemia was primarily monoclonal in the secondary recipient mice. Mutation analysis demonstrated that the protein tyrosine kinase activity of Bcr-Abl/p210 was essential for its leukemogenic potential in vivo. Interestingly, we found that the leukemic cells expressed excess interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the diseased mice. These studies demonstrate that expression of Bcr-Abl can induce a CML-like leukemia in mice much more efficiently and reproducibly than in previously reported mouse CML models, probably due to efficient expression in the correct target cell(s). Our first use of this model for analysis of the molecular mechanisms involved in CML raises the possibility that excess expression of hematopoietic growth factors such as IL-3 and GM-CSF may contribute to the clinical phenotype of CML.