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
基本信息
- 批准号:510825992
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:Research Units
- 财政年份:
- 资助国家:德国
- 起止时间:
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
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.
尽管对基因组的非蛋白质编码区域引起的大量转录本的研究增加了,但我们对非编码RNA的了解仍未在临床背景下应用。这种缺口与小儿急性髓样白血病(AML)特别相关,后者的治疗几乎没有改善,在三十年中,针对性的策略可以极大地改善长期治疗相关的毒性和与年轻患者的生活质量。 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 radiodicate self-renewing leukemia stem cells.We recently built a comprehensive resource defining the ncRNA landscape of the human hematopoietic system (www.lncscape.de)1并鉴定出由正常造血干细胞(HSC)和小儿白血病爆炸共享的核心NCRNA干细胞特征。由于已显示长期非编码RNA(LNCRNA)可以调节表观遗传和转录途径,因此我们假设来自核心干细胞签名的LNCRNA塑造了细胞染色质和转录景观,从而协调正常和恶性干细胞中的自我更新,增殖和差异。为了在此签名中识别与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完全基于CRISPRI的筛选策略。在两个或多个细胞环境中,有效且显着扰动白血病的生长有效地敲除了白血病的生长。因此,在这个项目中,我们将(1)表征5个高置信干细胞特异性的LNCRNA,这对于白血病进展至关重要,并且(2)解决其功能和机械特征。我们还将(3)评估以临床前RNA为中心的治疗干预措施,以克服当前的小儿AML治疗障碍。将这种恶性肿瘤的核心靶向可能导致癌症治疗的范式转移 - 将重点转移到影响和维持癌症的基本遗传程序,而不是致癌本身。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Professor Dr. Jan-Henning Cornelius Klusmann其他文献
Professor Dr. Jan-Henning Cornelius Klusmann的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Professor Dr. Jan-Henning Cornelius Klusmann', 18)}}的其他基金
Deciphering the genetic interactive network of the DLK1-DIO3 ncRNA locus in the hematopoietic system and in infant leukemias
破译造血系统和婴儿白血病中 DLK1-DIO3 ncRNA 位点的遗传相互作用网络
- 批准号:
354644272 - 财政年份:2017
- 资助金额:
-- - 项目类别:
Research Grants
From the pathogenesis to the therapy of infant leukemias
从婴儿白血病的发病机制到治疗
- 批准号:
355518855 - 财政年份:2017
- 资助金额:
-- - 项目类别:
Heisenberg Fellowships
Analyse nicht-kodierender RNAs als zentrale Regulatoren von Hämatopoese und Leukämogenese
作为造血和白血病发生的中央调节因子的非编码 RNA 的分析
- 批准号:
209828620 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Independent Junior Research Groups
Deciphering the complex, deregulated transcription network in the development of leukemia in children with Down syndrome
破译唐氏综合症儿童白血病发展过程中复杂的、失调的转录网络
- 批准号:
159893279 - 财政年份:2009
- 资助金额:
-- - 项目类别:
Research Grants
Deciphering the genetically interactive network of the DLK1-DIO3 ncRNA locus in the hematopoietic system and in infant leukemias
破译造血系统和婴儿白血病中 DLK1-DIO3 ncRNA 位点的遗传相互作用网络
- 批准号:
510825918 - 财政年份:
- 资助金额:
-- - 项目类别:
Research Units
Rewiring leukemogenic transformation of GATA1s-mediated CH by KANSL1 loss-of-function mutations (Project B4)
通过 KANSL1 功能丧失突变重新连接 GATA1s 介导的 CH 的白血病转化(项目 B4)
- 批准号:
533776703 - 财政年份:
- 资助金额:
-- - 项目类别:
Research Units
相似国自然基金
非编码驱动突变的癌种特异性和精确定位研究
- 批准号:
- 批准年份:2022
- 资助金额:54 万元
- 项目类别:面上项目
非编码驱动突变的癌种特异性和精确定位研究
- 批准号:32270717
- 批准年份:2022
- 资助金额:54.00 万元
- 项目类别:面上项目
基于多模态机器学习的非编码RNA定位预测
- 批准号:61972251
- 批准年份:2019
- 资助金额:60 万元
- 项目类别:面上项目
长链非编码RNA GTSE1-AS1 通过调控野生型P53蛋白胞内定位影响胰腺癌发生发展的机制研究
- 批准号:81902387
- 批准年份:2019
- 资助金额:20.0 万元
- 项目类别:青年科学基金项目
RNA结合蛋白介导长链非编码RNA亚细胞定位的机制研究
- 批准号:31900447
- 批准年份:2019
- 资助金额:25.0 万元
- 项目类别:青年科学基金项目
相似海外基金
Non-coding RNAs in resilience to Alzheimer’s Disease
非编码 RNA 有助于抵抗阿尔茨海默病
- 批准号:
10666167 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Cell-type specific and activity-dependent characterization of non-coding autism de novo variants in human stem cell-derived neurons
人类干细胞源性神经元中非编码自闭症从头变异的细胞类型特异性和活性依赖性表征
- 批准号:
10677459 - 财政年份:2023
- 资助金额:
-- - 项目类别: