Targeting the non-coding stem cell signature in childhood acute myeloid leukemia

靶向儿童急性髓系白血病的非编码干细胞特征

• 批准号: 510825992
• 负责人: Professor Dr. Jan-Henning Cornelius Klusmann
• 金额: --
• 依托单位: Klinik für Kinder- und Jugendmedizin
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/510825992?language=en
• 关键词: Targeting; non; coding; stem; cell

Despite increased research on the plethora of transcripts that arise from non-protein-coding regions of the genome, our knowledge of non-coding RNAs is still far from being applied in a clinical context. This shortfall is particularly relevant to pediatric acute myeloid leukemia (AML), the treatment of which has hardly improved in three decades, and for which targeted strategies stand to greatly ameliorate long-term treatment-related toxicities and quality of life for young patients. Understanding noncoding RNA (ncRNA)-mediated mechanisms of stem cell maintenance and how these processes are hijacked during malignant transformation is crucial for understanding the pathogenesis of leukemia, and will lay a foundation for developing novel targeted cancer-specific therapies that eradicate self-renewing leukemic stem cells.We recently built a comprehensive resource defining the ncRNA landscape of the human hematopoietic system (www.lncScape.de)1 and identified a core ncRNA stem cell signature shared by normal hematopoietic stem cells (HSCs) and pediatric leukemia blasts. Since long non-coding RNAs (lncRNAs) have been shown to regulate epigenetic and transcriptional pathways, we hypothesize that lncRNAs from the core stem cell signature shape the cellular chromatin and transcriptional landscape and thereby coordinate self-renewal, proliferation and differentiation in normal and malignant stem cells. To identify functionally relevant stem cell-specific lncRNAs within this signature, we applied two complementary CRISPRi-based screening strategies in vitro and in vivo. Knockdown of 17 lncRNA genes efficiently and significantly perturbed leukemic growth in two or more cellular contexts. In this project we will therefore (1) characterize 5 high confidence stem cell-specific lncRNAs that are essential for leukemia progression and (2) resolve their functional and mechanistic features. We will additionally (3) evaluate pre-clinical RNA-centered therapeutic interventions, with the aim of overcoming current obstacles in the treatment of pediatric AML. Targeting this malignancy at its core could lead to a paradigm shift in cancer treatment – shifting the focus to the underlying genetic programs that induce and sustain cancer, rather than the oncogenic hit itself.

尽管对基因组非蛋白质编码区域产生的大量转录本的研究有所增加，但我们对非编码 RNA 的了解仍远未应用于临床，这种不足与儿童急性髓性白血病尤其相关。 AML），该病的治疗在三十年来几乎没有改善，而针对该病的针对性策略将大大改善年轻患者的长期治疗相关毒性和生活质量。干细胞维持的机制以及这些过程在恶性转化过程中如何被劫持对于了解白血病的发病机制至关重要，并将为开发新的靶向癌症特异性疗法以根除自我更新的白血病干细胞奠定基础。我们最近建立了一个综合资源定义了人类造血系统的 ncRNA 景观 (www.lncScape.de)1 并确定了正常造血干细胞 (HSC) 和儿童白血病共有的核心 ncRNA 干细胞特征由于长非编码 RNA (lncRNA) 已被证明可以调节表观遗传和转录途径，因此我们利用来自核心干细胞特征的 lncRNA 塑造细胞染色质和转录景观，从而协调正常情况下的自我更新、增殖和分化。为了识别该特征中功能相关的干细胞特异性 lncRNA，我们在体外和体内应用了两种基于 CRISPRi 的互补筛选策略。因此，在这个项目中，我们将（1）表征对白血病进展至关重要的 5 种高置信度干细胞特异性 lncRNA，以及（2）解析它们的功能和机制特征。此外 (3) 评估以 RNA 为中心的临床前治疗干预措施，旨在克服目前治疗儿科 AML 的障碍，以这种恶性肿瘤为核心，可能会导致癌症治疗的范式转变——改变治疗的模式。重点关注诱发和维持癌症的潜在遗传程序，而不是致癌打击本身。