Fine-tuning patient-derived xenograft models for precision medicine approaches in leukemia.
Fine-tuning patient-derived xenograft models for precision medicine approaches in leukemia.
复制标题
通过白血病精确医学方法的微调患者衍生的异种移植模型。
DOI：
10.1136/jim-2016-000076
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发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Payne KJ
中科院分区：
文献类型：
--
作者：
Francis OL;Milford TA;Beldiman C;Payne KJ
许多白血病的特征是众所周知的驱动肿瘤发生的突变。用这些突变改造的小鼠为理解白血病发生和鉴定治疗方法提供了基础。然而，来自全基因组研究的数据提供了证据，表明恶性肿瘤的特征在于患者之间存在多种遗传变异，以及也可能导致肿瘤发生的遗传变异。改善的结果需要精确的医学方法-针对每个患者的恶性肿瘤的靶向治疗。需要反映患者群体中存在的突变范围和遗传背景的临床前模型来开发和测试将用于提供精确医学治疗策略的治疗组合。通过将来自患者的白血病细胞移植到免疫缺陷小鼠中产生的患者来源的异种移植物（PDX）提供了临床前模型，其中可以在患者肿瘤中存在的遗传变异性的背景下在体内研究疾病机制和治疗功效。PDX模型是可能的，因为骨髓微环境中的许多元素显示出小鼠和人类之间的跨物种活性。然而，可能影响白血病细胞的几种细胞因子是物种特异性的，对移植的人白血病细胞的活性有限。在这篇综述中，我们讨论了PDX模型对开发白血病治疗的精确医学方法的重要性。我们说明了如何PDX模型可以被优化，以克服缺乏跨物种的细胞因子活性，通过审查最近的策略开发用于与高风险形式的B细胞急性淋巴细胞白血病（B-ALL），其特征是CRLF 2，细胞因子，TSLP的受体成分的过表达。
Many leukemias are characterized by well-known mutations that drive oncogenesis. Mice engineered with these mutations provide a foundation for understanding leukemogenesis and identifying therapies. However, data from whole genome studies provide evidence that malignancies are characterized by multiple genetic alterations that vary between patients, as well as inherited genetic variation that can also contribute to oncogenesis. Improved outcomes will require precision medicine approaches–targeted therapies tailored to malignancies in each patient. Preclinical models that reflect the range of mutations and the genetic background present in patient populations are required to develop and test the combinations of therapies that will be used to provide precision medicine therapeutic strategies. Patient-derived xenografts (PDX) produced by transplanting leukemia cells from patients into immune deficient mice provide preclinical models where disease mechanisms and therapeutic efficacy can be studied in vivo in context of the genetic variability present in patient tumors. PDX models are possible because many elements in the bone marrow microenvironment show cross-species activity between mice and humans. However, several cytokines likely to impact leukemia cells are species-specific with limited activity on transplanted human leukemia cells. In this review we discuss the importance of PDX models for developing precision medicine approaches to leukemia treatment. We illustrate how PDX models can be optimized to overcome a lack of cross-species cytokine activity by reviewing a recent strategy developed for use with a high-risk form of B-cell acute lymphoblastic leukemia (B-ALL) that is characterized by overexpression of CRLF2, a receptor component for the cytokine, TSLP.
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