Targeting the Ferroptosis regulatory network in multiple myeloma and hematologicalmalignancies

多发性骨髓瘤（Multiple myeloma， MM）是一种目前仍无法治愈的B细胞疾病，主要由恶性浆细胞在骨髓中积聚和扩增引起，但不限于骨髓。目前的标准治疗是基于多种联合治疗方法，包括化疗药物、皮质类固醇、蛋白酶体抑制剂、免疫调节药物和针对CD38和CD319的单克隆抗体。然而，大多数患者在治疗过程中产生耐药性，最终死于疾病。因此，评估新的治疗方法仍然是一项具有挑战性的任务。我们假设，最近发现的一种细胞死亡方式——铁凋亡的靶向治疗可能代表了一种新的治疗策略，因为它已被证明可以诱导化疗难治性癌细胞的细胞死亡。自己的初步数据显示，新发现的铁下垂调节因子铁下垂抑制蛋白1 （FSP1）在人MM细胞系和MM患者的原代细胞中表达。此外，我们观察到FSP1在MM细胞系中过表达支持细胞在一系列代谢相关应激条件下的生长。为了表征铁下垂和FSP1作为MM的潜在治疗靶点，我们的目标是在我们的应用中实现以下目标：i)表征铁下垂在MM中的调节，特别是关于对铁下垂介导的细胞死亡的敏感性，ii) FSP1的作用和转录调节，以及iii) FSP1在MM小鼠模型中治疗诱导和代谢应激条件下MM细胞生长的作用。

Multiple myeloma (MM) is a still largely incurable B cell disease caused by accumulation and expansion of malignant plasma cells mainly in but not restricted to bone marrow. Current standard treatment is based on a number of combination approaches including chemotherapeutic agents, corticosteroids, proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies against CD38 and CD319. However, most patients develop drug resistance during the course of therapy and eventually succumb to the disease. Therefore, evaluation of novel therapeutic approaches remains a challenging task. We hypothesize that targeting of ferroptosis, a recently discovered cell death modality, might represent such a novel treatment strategy, because it has been shown to induce cell death in chemotherapy-refractory cancer cells. Own preliminary data revealed expression of the newly identified ferroptosis regulator Ferroptosis Suppressor Protein 1 (FSP1) in human MM cell lines and in primary cells from MM patients. In addition, we observed that overexpression of FSP1 in MM cell lines supports cell growth under a range of metabolically relevant stress conditions. In order to characterize ferroptosis and FSP1 as a potential therapeutic target in MM, we aim to achieve the following objectives in our application: i) characterization of ferroptosis regulation in MM, in particular in regards to sensitivity towards ferroptosis-mediated cell death, ii) the role and transcriptional regulation of FSP1, and iii) the role of FSP1 for the growth of MM cells under therapy-induced and metabolic stress conditions in MM mouse models.