Core transcriptional regulators of malignant stem cell generation in multiple myeloma

摘要 多发性骨髓瘤是一种致命的浆细胞肿瘤，其特征是异常的骨髓瘤细胞恶性扩张。 抗体生成细胞尽管最近的治疗进展，大多数患者最终复发。如此之高- 高危患者的总存活率通常小于一年。这些不良的临床结局发生在 这是恶性干细胞样细胞在保护性、炎症性和免疫性疾病中不受控制的再生的结果。 微环境然而，骨髓瘤骨髓干细胞的精确转录决定因素 骨髓龛仍然知之甚少。一个有趣的候选者是关键的B细胞转录因子， 骨髓瘤细胞存活因子，干扰素应答因子-4（IRF 4）。IRF 4也控制正常的浆细胞 然而，IRF 4促进恶性肿瘤的程度， 淋巴或浆细胞肿瘤中的祖细胞生成是未知的。IRF 4表达减少50% 可以破坏骨髓瘤细胞的存活，但IRF 4作为治疗靶点尚未开发，因为转录 使用传统的小分子策略难以抑制这些因子。为了克服这一挑战， 进行了概念研究，以评价直接抑制人类的新的RNA靶向治疗剂， IRF 4 RNA表达和蛋白质翻译。基于广泛的初步数据， 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 IRF 4的抑制将破坏多发性骨髓瘤中的干细胞途径活化， 标准治疗药物，以减少整体疾病负担和预防恶性干细胞生成。在 在三个独立但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：审讯 IRF 4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IRF 4与骨髓瘤再生联系起来。目的2：IRF 4抑制剂单药治疗和联合药物治疗 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志物 利用选择性IRF 4抑制的检测策略。目的3：阐明骨髓 微环境来源的信号，促进骨髓瘤再生中的IRF 4途径活化。这一目标将 阐明骨髓瘤再生的旁分泌机制和一种新癌症的活性 有治疗作用的拟议的研究将为更有选择性的快速临床翻译奠定基础。 骨髓瘤的联合治疗。研究小组联合癌症和干细胞生物学专家， 临床医生和合作者，他们在癌症新疗法的翻译方面经验丰富。 总之，该项目旨在推进IRF 4抑制剂治疗的快速临床转化， 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.