Core transcriptional regulators of malignant stem cell generation in multiple myeloma

摘要 多发性骨髓瘤是一种以恶性扩张为特征的致死性浆细胞肿瘤。 抗体产生细胞。尽管最近在治疗上取得了进展，但大多数患者最终还是会复发。如此之高- 高风险患者的总体存活率通常不到一年。这些不良的临床结果发生在 保护性、炎症性的恶性干细胞样细胞不受控制的再生的结果 微环境。然而，骨髓瘤干细胞的准确转录决定因素 骨髓生态位仍然鲜为人知。一个耐人寻味的候选者是一个关键的B细胞转录因子和 骨髓瘤细胞存活因子、干扰素反应因子-4(IRF4)。IRF4也控制正常的浆细胞 炎症的发生和免疫反应，然而IRF4促进恶性的程度 淋巴系或浆细胞肿瘤的祖细胞生成尚不清楚。IRF4表达减少50% 可以干扰骨髓瘤细胞的存活，但由于转录，IRF4作为治疗靶点仍未开发出来 使用传统的小分子策略很难抑制这些因素。为了克服这一挑战，证明- 开展概念性研究，以评估直接抑制人类免疫功能的新型RNA靶向治疗剂 IRF4的RNA表达和蛋白质翻译。基于大量初步数据，这些数据描述了IRF4 在临床相关的体外和体内模型中的表达和活性，该项目的中心假设是 抑制IRF4将破坏多发性骨髓瘤干细胞途径的激活，并与 降低总体疾病负担和防止恶性干细胞产生的标准护理药物。在 在三个独立但在概念上相互关联的目标的背景下，这一假设将在 通过严格的科学方法进行全面的分子和细胞分析。目标1：审问 IRF4在功能性骨髓瘤干细胞生成中的作用。这一目标将决定细胞的内在机制 将IRF4与骨髓瘤再生联系起来。目的2：IRF4抑制剂单药治疗和联合用药治疗 多发性骨髓瘤的临床前模型。这一目标将开发联合药物治疗和生物标记物 利用选择性IRF4抑制的检测策略。目的3：阐明骨髓 促进骨髓瘤再生中IRF4途径激活的微环境衍生信号。这一目标将 阐明骨髓瘤再生的旁分泌机制和一种新肿瘤的活性 有治疗作用。拟议的研究将为更具选择性的快速临床翻译奠定基础 骨髓瘤的综合疗法。研究小组联合了癌症和干细胞生物学专家骨髓瘤 临床医生，以及在癌症新疗法翻译方面经验丰富的合作者。 总之，该项目旨在推动IRF4抑制剂疗法在临床上的快速转化 骨髓瘤。这些研究还将为靶向恶性干细胞的产生开辟新的途径 其他癌症和炎症相关疾病。

ABSTRACT Multiple myeloma is a fatal plasma cell neoplasm that is characterized by the malignant expansion of abnormal antibody-producing cells. Despite recent therapeutic advances, most patients eventually relapse. Such high- risk patients typically have an overall survival rate of less than one year. These poor clinical outcomes occur as a result of uncontrolled regeneration of malignant stem-like cells in protective, inflammatory microenvironments. However, the precise transcriptional determinants of myeloma stemness in the bone marrow niche remain poorly understood. One intriguing candidate is a key B-cell transcription factor and myeloma cell survival factor, interferon response factor-4 (IRF4). IRF4 also governs normal plasma cell development and immune responses to inflammation, however the extent to which IRF4 promotes malignant progenitor generation in lymphoid or plasma cell neoplasms is unknown. A 50% reduction in IRF4 expression can disrupt myeloma cell survival, but IRF4 remains undeveloped as a therapeutic target because transcription factors are difficult to inhibit using traditional small molecule strategies. To overcome this challenge, proof-of- concept studies were performed to evaluate novel RNA-targeted therapeutic agents that directly inhibit human IRF4 RNA expression and protein translation. Based on extensive preliminary data that characterized IRF4 expression and activity in clinically-relevant in vitro and in vivo models, the central hypothesis of this project is that inhibition of IRF4 will disrupt stem cell pathway activation in multiple myeloma and synergize with standard-of-care drugs to reduce overall disease burden and prevent malignant stem cell generation. In the context of three independent yet conceptually interrelated aims, this hypothesis will be tested in comprehensive molecular and cellular assays through a rigorous scientific approach. Aim 1: Interrogating the role of IRF4 in functional myeloma stem cell generation. This aim will determine the cell-intrinsic mechanisms that link IRF4 to myeloma regeneration. Aim 2: IRF4 inhibitor monotherapy and combination drug treatment in pre-clinical models of multiple myeloma. This aim will develop combination drug treatment and biomarker detection strategies that leverage selective IRF4 inhibition. Aim 3: Elucidating the bone marrow microenvironment-derived signals that promote IRF4 pathway activation in myeloma regeneration. This aim will elucidate the paracrine mechanisms underlying myeloma regeneration and the activity of a novel cancer therapeutic. The proposed research will set the stage for rapid clinical translation of more selective combination therapies for myeloma. The research team unites cancer and stem cell biology experts, myeloma clinicians, and collaborators who are highly experienced in the translation of novel therapeutics for cancer. Together, this project is positioned to advance the rapid clinical translation of IRF4 inhibitor therapy for myeloma. These investigations will also open up new avenues for targeting malignant stem cell generation in other cancers and inflammation-associated diseases.