Weisberg Ellen, Wright Renee D, McMillin Douglas W, Mitsiades Constantine, Ray Arghya, Barrett Rosemary, Adamia Sophia, Stone Richard, Galinsky Ilene, Kung Andrew L, Griffin James D
Department of Medical Oncology/Hematologic Neoplasia, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
Mol Cancer Ther. 2008 May;7(5):1121-9. doi: 10.1158/1535-7163.MCT-07-2331. Epub 2008 Apr 29.
Clinical studies of patients with chronic myeloid leukemia revealed that a common pattern of response is a dramatic fall in the circulating population of blast cells, with a minimal or delayed decrease in marrow blasts, suggesting a protective environment. These observations suggest that a greater understanding of the interaction of stromal cells with leukemic cells is essential. Here, we present an in vivo system for monitoring relative tumor accumulation in leukemic mice and residual disease in leukemic mice treated with a tyrosine kinase inhibitor and an in vitro system for identifying integral factors involved in stromal-mediated cytoprotection. Using the in vivo model, we observed high tumor burden/residual disease in tissues characterized as significant sources of hematopoiesis-promoting stroma, with bone marrow stroma most frequently showing the highest accumulation of leukemia in untreated and nilotinib-treated mice as well as partial protection of leukemic cells from the inhibitory effects of nilotinib. These studies, which showed a pattern of leukemia distribution consistent with what is observed in imatinib- and nilotinib-treated chronic myeloid leukemia patients, were followed by a more in-depth analysis of stroma-leukemia cell interactions that lead to protection of leukemia cells from nilotinib-induced cytotoxicity. For the latter, we used the human BCR-ABL-positive cell line, KU812F, and the human bone marrow stroma cell line, HS-5, to more closely approximate the bone marrow-associated cytoprotection observed in drug-treated leukemia patients. This in vitro system helped to elucidate stromal-secreted viability factors that may play a role in stromal-mediated cytoprotection of tyrosine kinase inhibitor-treated leukemia cells.
对慢性髓性白血病患者的临床研究表明，常见的反应模式是循环中的原始细胞数量急剧下降，而骨髓原始细胞数量减少最少或延迟，这表明存在一个保护环境。这些观察结果表明，更深入了解基质细胞与白血病细胞之间的相互作用至关重要。在此，我们展示了一种用于监测白血病小鼠体内相对肿瘤积累以及用酪氨酸激酶抑制剂治疗的白血病小鼠残留疾病的体内系统，以及一种用于鉴定参与基质介导的细胞保护的整合因子的体外系统。使用体内模型，我们在被确定为促进造血基质的重要来源的组织中观察到高肿瘤负荷/残留疾病，在未治疗和尼洛替尼治疗的小鼠中，骨髓基质最常显示白血病的最高积累，以及白血病细胞对尼洛替尼抑制作用的部分保护。这些研究显示白血病分布模式与在伊马替尼和尼洛替尼治疗的慢性髓性白血病患者中观察到的一致，随后对导致白血病细胞免受尼洛替尼诱导的细胞毒性保护的基质 - 白血病细胞相互作用进行了更深入的分析。对于后者，我们使用人BCR-ABL阳性细胞系KU812F和人骨髓基质细胞系HS-5，以更接近地模拟在药物治疗的白血病患者中观察到的与骨髓相关的细胞保护。这个体外系统有助于阐明可能在酪氨酸激酶抑制剂治疗的白血病细胞的基质介导的细胞保护中起作用的基质分泌的存活因子。
