Dartmouth Health Cancer Center, Department of Pediatrics, Geisel School of Medicine at Dartmouth College, Lebanon, NH, United States of America.
Department of Biomedical Data Science, Geisel School of Medicine, Lebanon, NH, United States of America.
PLoS One. 2024 Jan 30;19(1):e0292375. doi: 10.1371/journal.pone.0292375. eCollection 2024.
Fanconi anemia (FA)-mutated acute myeloid leukemia (AML) is a secondary AML with very poor prognosis and limited therapeutic options due to increased sensitivity to DNA-damaging agents. PD-1 immune checkpoint inhibitors upregulate T-cell killing of cancer cells and is a class of promising treatment for FA-AML. Here, we developed a novel FA-AML murine model that allows the study of human AML with a humanized immune system in order to investigate immunotherapeutic treatments in vivo. FA-AML1 cells and non-FA-mutated Kasumi-1 cells were injected into 8-10 week old NSG mice. Once leukemic engraftment was confirmed by HLA-DR expression in the peripheral blood, human peripheral blood mononuclear cells (hPBMCs) were injected into the mice. One week post-hPBMCs injection, Nivolumab (PD-1 inhibitor) or PBS vehicle control was administered to the mice bi-weekly. In our Nivolumab treated mice, FA-AML1, but not Kasumi-1-engrafted mice, had significantly prolonged overall survival. Both FA-AML1 and Kasumi-1 engrafted mice had decreased spleen weights. Higher leukemic infiltration into vital organs was observed in FA-AML1 engrafted mice compared to Kasumi-1 engrafted mice. In conclusion, our novel humanized murine model of FA-mutated AML is an attractive tool for supporting further studies and clinical trials using PD-1 inhibitors to treat FA-mutated AML.
范可尼贫血（FA）突变急性髓系白血病（AML）是一种继发性 AML，由于对 DNA 损伤剂的敏感性增加，预后非常差，治疗选择有限。PD-1 免疫检查点抑制剂上调 T 细胞对癌细胞的杀伤作用，是一类有前途的 FA-AML 治疗方法。在这里，我们开发了一种新型的 FA-AML 小鼠模型，该模型允许在具有人类化免疫系统的情况下研究人类 AML，以便在体内研究免疫治疗方法。将 FA-AML1 细胞和非 FA 突变的 Kasumi-1 细胞注射到 8-10 周龄的 NSG 小鼠中。一旦通过外周血中 HLA-DR 的表达确认白血病植入，就将人外周血单核细胞（hPBMC）注入小鼠中。在 hPBMC 注射后一周，每周两次向小鼠给予 Nivolumab（PD-1 抑制剂）或 PBS 载体对照。在我们用 Nivolumab 治疗的小鼠中，FA-AML1 而非 Kasumi-1 植入的小鼠的总生存期明显延长。FA-AML1 和 Kasumi-1 植入的小鼠的脾脏重量均减轻。与 Kasumi-1 植入的小鼠相比，FA-AML1 植入的小鼠观察到更多的白血病浸润到重要器官。总之，我们新型的 FA 突变 AML 人源化小鼠模型是支持使用 PD-1 抑制剂治疗 FA 突变 AML 的进一步研究和临床试验的有吸引力的工具。
