Section of Hematology, Department of Internal Medicine and Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA.
Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
Nat Commun. 2019 Jan 21;10(1):366. doi: 10.1038/s41467-018-08166-x.
Comprehensive preclinical studies of Myelodysplastic Syndromes (MDS) have been elusive due to limited ability of MDS stem cells to engraft current immunodeficient murine hosts. Here we report a MDS patient-derived xenotransplantation model in cytokine-humanized immunodeficient "MISTRG" mice that provides efficient and faithful disease representation across all MDS subtypes. MISTRG MDS patient-derived xenografts (PDX) reproduce patients' dysplastic morphology with multi-lineage representation, including erythro- and megakaryopoiesis. MISTRG MDS-PDX replicate the original sample's genetic complexity and can be propagated via serial transplantation. MISTRG MDS-PDX demonstrate the cytotoxic and differentiation potential of targeted therapeutics providing superior readouts of drug mechanism of action and therapeutic efficacy. Physiologic humanization of the hematopoietic stem cell niche proves critical to MDS stem cell propagation and function in vivo. The MISTRG MDS-PDX model opens novel avenues of research and long-awaited opportunities in MDS research.
由于 MDS 干细胞在当前免疫缺陷的鼠类宿主中植入的能力有限，因此对骨髓增生异常综合征 (MDS) 的全面临床前研究一直难以实现。在这里，我们报告了一种 MDS 患者来源的异种移植模型，在细胞因子人源化免疫缺陷的“MISTRG”小鼠中，该模型能够在所有 MDS 亚型中提供高效和真实的疾病表现。MISTRG MDS 患者来源的异种移植物 (PDX) 再现了患者的多谱系发育异常形态，包括红细胞生成和巨核细胞生成。MISTRG MDS-PDX 复制了原始样本的遗传复杂性，并可通过连续移植进行传播。MISTRG MDS-PDX 证明了靶向治疗的细胞毒性和分化潜力，为药物作用机制和治疗效果提供了更好的检测结果。造血干细胞龛的生理性人源化对于 MDS 干细胞在体内的增殖和功能至关重要。MISTRG MDS-PDX 模型为 MDS 研究开辟了新的研究途径和长期以来的机会。
