PDF(Pubmed)
Abstract：
Aggressive natural killer cell leukemia (ANKL) is a rare hematological malignancy with a fulminant clinical course. Our previous study revealed that ANKL cells proliferate predominantly in the liver sinusoids and strongly depend on transferrin supplementation. In addition, we demonstrated that liver-resident ANKL cells are sensitive to PPMX-T003, an anti-human transferrin receptor 1 inhibitory antibody, whereas spleen-resident ANKL cells are resistant to transferrin receptor 1 inhibition. However, the microenvironmental factors that regulate the iron dependency of ANKL cells remain unclear. In this study, we first revealed that the anti-neoplastic effect of PPMX-T003 was characterized by DNA double-strand breaks in a DNA replication-dependent manner, similar to conventional cytotoxic agents. We also found that the influx of extracellular amino acids via LAT1 stimulated sensitivity to PPMX-T003. Taken together, we discovered that the amount of extracellular amino acid influx through LAT1 was the key environmental factor determining the iron dependency of ANKL cells via adjustment of their mTOR/Myc activity, which provides a good explanation for the different sensitivity to PPMX-T003 between liver- and spleen-resident ANKL cells, as the liver sinusoid contains abundant amino acids absorbed from the gut.
摘要：
侵袭性自然杀伤细胞白血病（ANKL）是一种罕见的血液恶性肿瘤，具有暴发性临床病程。我们先前的研究表明，ANKL细胞主要在肝窦中增殖，并且强烈依赖于转铁蛋白的补充。此外,我们证明了肝脏驻留的ANKL细胞对PPMX-T003敏感，PPMX-T003是一种抗人转铁蛋白受体1抑制性抗体，而脾脏驻留的ANKL细胞对转铁蛋白受体1抑制具有抗性。然而,调节ANKL细胞铁依赖性的微环境因素尚不清楚.在这项研究中,我们首先揭示了PPMX-T003的抗肿瘤作用以DNA复制依赖性方式的DNA双链断裂为特征，类似于传统的细胞毒性剂。我们还发现，通过LAT1的细胞外氨基酸流入刺激了对PPMX-T003的敏感性。一起来看,我们发现通过LAT1的细胞外氨基酸流入量是通过调节其mTOR/Myc活性决定ANKL细胞铁依赖性的关键环境因素，这为肝脏和脾脏驻留的ANKL细胞对PPMX-T003的不同敏感性提供了很好的解释，因为肝窦含有从肠道吸收的丰富氨基酸。
