Penn State Cancer Institute, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
Department of Pathology, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
J Leukoc Biol. 2022 Feb;111(2):427-437. doi: 10.1002/JLB.5AB0820-542RR. Epub 2021 May 31.
The prognosis for acute myeloid leukemia (AML) relapse post allogeneic hematopoietic stem cell transplantation (alloSCT) is dismal. Novel effective treatment is urgently needed. Clinical benefit of alloSCT greatly relies on the graft-versus-leukemia (GVL) effect. The mechanisms that mediate immune escape of leukemia (thus causing GVL failure) remain poorly understood. Studies of human GVL have been hindered by the lack of optimal clinically relevant models. Here, using our large, longitudinal clinical tissue bank that include AML cells and G-CSF mobilized donor hematopoietic stem cells (HSCs), we successfully established a novel GVL model in humanized mice. Donor HSCs were injected into immune-deficient NOD-Cg-Prkdc IL2rg /SzJ (NSG) mice to build humanized mice. Immune reconstitution in these mice recapitulated some clinical scenario in the patient who received the corresponding HSCs. Allogeneic but HLA partially matched patient-derived AML cells were successfully engrafted in these humanized mice. Importantly, we observed a significantly reduced (yet incomplete elimination of) leukemia growth in humanized mice compared with that in control NSG mice, demonstrating a functional (but defective) GVL effect. Thus, for the first time, we established a novel humanized mouse model that can be used for studying human GVL responses against human AML cells in vivo. This novel clinically relevant model provides a valuable platform for investigating the mechanisms of human GVL and development of effective leukemia treatments.
异基因造血干细胞移植（alloSCT）后急性髓系白血病（AML）复发的预后较差。迫切需要新的有效治疗方法。alloSCT 的临床获益很大程度上依赖于移植物抗白血病（GVL）效应。介导白血病免疫逃逸（从而导致 GVL 失败）的机制仍知之甚少。由于缺乏最佳的临床相关模型，人类 GVL 的研究受到阻碍。在这里，我们使用包含 AML 细胞和 G-CSF 动员供体造血干细胞（HSCs）的大型纵向临床组织库，成功地在人源化小鼠中建立了一种新型 GVL 模型。将供体 HSCs 注入免疫缺陷型 NOD-Cg-Prkdc IL2rg /SzJ（NSG）小鼠中以构建人源化小鼠。这些小鼠中的免疫重建再现了接受相应 HSCs 的患者的某些临床情况。异基因但 HLA 部分匹配的患者来源 AML 细胞成功地在这些人源化小鼠中植入。重要的是，与对照 NSG 小鼠相比，我们观察到人源化小鼠中的白血病生长明显减少（但未完全消除），这表明存在功能性（但有缺陷的）GVL 效应。因此，我们首次建立了一种新型人源化小鼠模型，可用于体内研究人类 GVL 对人类 AML 细胞的反应。这种新型临床相关模型为研究人类 GVL 的机制和开发有效的白血病治疗方法提供了有价值的平台。
