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Abstract：
Multiple myeloma (MM) is a hematologic malignancy with a multistep evolutionary pattern, in which the pro-inflammatory and immunosuppressive microenvironment and genomic instability drive tumor evolution. MM microenvironment is rich in iron, released by pro-inflammatory cells from ferritin macromolecules, which contributes to ROS production and cellular damage. In this study, we showed that ferritin increases from indolent to active gammopathies and that patients with low serum ferritin had longer first line PFS (42.6 vs. 20.7 months and, p = 0.047, respectively) and OS (NR vs. 75.1 months and p = 0.029, respectively). Moreover, ferritin levels correlated with systemic inflammation markers and with the presence of a specific bone marrow cell microenvironment (including increased MM cell infiltration). Finally, we verified by bioinformatic approaches in large transcriptomic and single cell datasets that a gene expression signature associated with ferritin biosynthesis correlated with worse outcome, MM cell proliferation, and specific immune cell profiles. Overall, we provide evidence of the role of ferritin as a predictive/prognostic factor in MM, setting the stage for future translational studies investigating ferritin and iron chelation as new targets for improving MM patient outcome.
摘要：
多发性骨髓瘤（MM）是一种血液系统恶性肿瘤，具有多步进化模式，其中促炎和免疫抑制微环境和基因组不稳定性驱动肿瘤进化。MM微环境富含铁，从铁蛋白大分子中释放促炎细胞，这有助于ROS的产生和细胞损伤。在这项研究中,我们显示，铁蛋白从惰性到活动性丙种球蛋白增加，血清铁蛋白低的患者的一线PFS更长（42.6vs.20.7个月和，分别为p=0.047)和OS(NR与分别为75.1个月和p=0.029）。此外，铁蛋白水平与全身炎症标志物和特定骨髓细胞微环境(包括增加的MM细胞浸润)的存在相关。最后,我们通过生物信息学方法在大型转录组和单细胞数据集中验证了与铁蛋白生物合成相关的基因表达特征与较差的结果相关。MM细胞增殖，和特定的免疫细胞谱。总的来说,我们提供了铁蛋白作为MM预测/预后因子的作用的证据，为研究铁蛋白和铁螯合作为改善MM患者预后的新靶点的未来转化研究奠定了基础。
