Establishment of a murine model for therapy-treated chronic myelogenous leukemia using the tyrosine kinase inhibitor STI571
Establishment of a murine model for therapy-treated chronic myelogenous leukemia using the tyrosine kinase inhibitor STI571
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DOI：
10.1182/blood.v98.9.2808
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发表时间：
2001-11-01
期刊：
影响因子：
20.3
通讯作者：
Ilaria, RL
中科院分区：
文献类型：
--
作者：
Wolff, NC;Ilaria, RL
慢性粒细胞白血病 (CML) 的小鼠骨髓逆转录病毒转导和移植模型不能完美地模拟人类 CML，因为小鼠 CML 样疾病会导致所有动物在 3 至 4 周内因压倒性粒细胞增多症而死亡。在本报告中，用 P210(BCR/ABL) 转导的骨髓细胞重建的小鼠接受了酪氨酸激酶抑制剂 STI571 或安慰剂的移植后治疗。与安慰剂治疗的动物迅速致命的白血病相比，STI571治疗的小鼠在第74天有80%存活，外周白细胞计数和脾肿大显着改善。 STI571 治疗动物的白血病细胞中 STAT5、Shc 和 Crk-L 的酪氨酸磷酸化降低，这与 STI571 介导的体内 Bcr/Abl 酪氨酸激酶抑制一致。在一些 STI571 治疗的动物中，Bcr/Abl 信使 RNA 和蛋白质表达显着增加。与安慰剂治疗小鼠的多克隆白血病相反，STI571治疗的小鼠CML通常是寡克隆的，这表明STI571消除或严重抑制了某些白血病克隆。然而，STI571 治疗的小鼠中没有一只能够治愈 CML 样骨髓增殖性疾病，并且 STI571 治疗的小鼠 CML 被高效地移植到二级受体中。这些结果证明了这种 CML 小鼠模型在评估针对 Bcr/Abl 诱导的白血病的新型治疗药物中的效用。这种改进的小鼠慢性期 CML 模型可能是研究 STI571 耐药性、CML 进展和抗 CML 免疫反应的有用工具。 (C) 2001 年，美国血液学会。
The murine bone marrow retroviral transduction and transplantation model of chronic myelogenous leukemia (CML) imperfectly mimics human CML because the murine CML-like disease causes death of all animals from an overwhelming granulocytosis within 3 to 4 weeks. In this report, mice reconstituted with P210(BCR/ABL) transduced bone marrow cells received posttransplantation therapy with either the tyrosine kinase inhibitor STI571 or placebo. Compared with the rapidly fatal leukemia of placebo-treated animals, 80% of the STI571-treated mice were alive on day 74, with marked improvement in peripheral white blood counts and splenomegaly. There was decreased tyrosine phosphorylation of STAT5, Shc, and Crk-L in leukemic cells from STI571-treated animals, consistent with STI571-mediated inhibition of the Bcr/Abl tyrosine kinase in vivo. In some STI571-treated animals Bcr/Abl messenger RNA and protein expression were markedly increased. In contrast to the polyclonal leukemia of placebo-treated mice, STI571-treated murine CML was generally oligoclonal, suggesting that STI571 eliminated or severely suppressed certain leukemic clones. None of the STI571-treated mice were cured of the CML-like myeloproliferative disorder, however, and STI571-treated murine CML was transplanted to secondary recipients with high efficiency. These results demonstrate the utility of this murine model of CML in the evaluation of novel therapeutic agents against Bcr/Abl-induced leukemias. This improved murine chronic-phase CML model may be a useful tool for the study of STI571 resistance, CML progression, and the anti-CML Immune response. (C) 2001 by The American Society of Hematology.