Johnson Amy J, Lucas David M, Muthusamy Natarajan, Smith Lisa L, Edwards Ryan B, De Lay Michael D, Croce Carlo M, Grever Michael R, Byrd John C
Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
Blood. 2006 Aug 15;108(4):1334-8. doi: 10.1182/blood-2005-12-011213. Epub 2006 May 2.
Drug development in human chronic lymphocytic leukemia (CLL) has been limited by lack of a suitable animal model to adequately assess pharmacologic properties relevant to clinical application. A recently described TCL-1 transgenic mouse develops a chronic B-cell CD5(+) leukemia that might be useful for such studies. Following confirmation of the natural history of this leukemia in the transgenic mice, we demonstrated that the transformed murine lymphocytes express relevant therapeutic targets (Bcl-2, Mcl-1, AKT, PDK1, and DNMT1), wild-type p53 status, and in vitro sensitivity to therapeutic agents relevant to the treatment of human CLL. We then demonstrated the in vivo clinical activity of low-dose fludarabine in transgenic TCL-1 mice with active leukemia. These studies demonstrated both early reduction in blood-lymphocyte count and spleen size and prolongation of survival (P = .046) compared with control mice. Similar to human CLL, an emergence of resistance was noted with fludarabine treatment in vivo. Overall, these studies suggest that the TCL-1 transgenic leukemia mouse model has similar clinical and therapeutic response properties to human CLL and may therefore serve as a useful in vivo tool to screen new drugs for subsequent development in CLL.
人类慢性淋巴细胞白血病（CLL）的药物研发一直受到限制，因为缺乏合适的动物模型来充分评估与临床应用相关的药理学特性。最近描述的TCL-1转基因小鼠会发生慢性B细胞CD5(+)白血病，可能对这类研究有用。在确认了这种白血病在转基因小鼠中的自然病程后，我们证明转化的小鼠淋巴细胞表达相关治疗靶点（Bcl-2、Mcl-1、AKT、PDK1和DNMT1）、野生型p53状态，以及对与人类CLL治疗相关的治疗药物的体外敏感性。然后我们证明了低剂量氟达拉滨在患有活动性白血病的转基因TCL-1小鼠中的体内临床活性。与对照小鼠相比，这些研究表明血液淋巴细胞计数和脾脏大小均早期降低，生存期延长（P = 0.046）。与人类CLL相似，体内氟达拉滨治疗出现了耐药性。总体而言，这些研究表明TCL-1转基因白血病小鼠模型与人类CLL具有相似的临床和治疗反应特性，因此可能作为一种有用的体内工具来筛选新药，以供后续在CLL中进行开发。
