Characterization of the hierarchical organisation of MLL leukemias and pharmacological targeting of key signalling pathways and epigenetic enzymes in human MLL leukemia stem cells.
MLL 白血病分层组织的表征以及人 MLL 白血病干细胞中关键信号通路和表观遗传酶的药理学靶向。
基本信息
- 批准号:215322340
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:Research Fellowships
- 财政年份:2011
- 资助国家:德国
- 起止时间:2010-12-31 至 2013-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Balanced chromosomal translocations play an important role in the pathogenesis of leukemias. Chromosomal translocations involving the MLL gene located on chromosome band 11q23 are implicated in childhood and adult leukemias and therapy-related leukemia. These translocations are associated with unique clinical and biological characteristics and lead to pathogenesis of acute leukemias with both lymphoid (ALL) and myeloid (AML) phenotype. Currently, more than 50 MLL fusion partner genes are described. They induce a corrupted transcriptional program including the aberrant expression of homeobox (HOX) related genes and the epigenetic regulation of other MLL target genes through recruitment of chromatin-modifying enzymes, including histone methyltransferases (HMTs) and protein arginine methyltransferases (PRMTs). The cancer stem cell hypothesis suggests that the origin and maintenance of a leukemic clone depends on a rare cell population at the apex of the cellular hierarchy with indefinite potential for self-renewal, the leukemia stem cells (LSCs). Signaling pathways aberrantly activated, including the GSK3- and Wnt/b-catenin-pathway, confer self-renewal, proliferative and anti-apoptotic properties to MLL leukemia cells. The goal of this project is the characterization of the malignant/aberrant hierarchical organisation and signaling properties of LSC subpopulations in primary patient samples and well-characterized MLL leukemia models. LSC frequencies and hierarchical relationships will dynamically be tracked at baseline and in response to pharmacological signaling and epigenetic targeting of MLL LSCs using mass cytometry (CYTOF) and xenotransplantation models. The epigenetic and signaling targeting of MLL leukemia stem cells has clinical implications and will allow the development of clinical therapies to eradicate this cell subpopulation and to improve the prognosis of patients bearing MLL translocations.
平衡染色体易位在白血病的发病机制中起重要作用。涉及位于染色体带11q23上的MLL基因的染色体易位与儿童和成人白血病以及治疗相关白血病有关。这些易位与独特的临床和生物学特征相关,并导致淋巴(ALL)和骨髓(AML)表型的急性白血病的发病机制。目前,已知的MLL融合伴侣基因超过50个。它们通过募集染色质修饰酶,包括组蛋白甲基转移酶(HMTs)和蛋白精氨酸甲基转移酶(PRMTs),诱导一个错误的转录程序,包括同源框(HOX)相关基因的异常表达和其他MLL靶基因的表观遗传调控。癌症干细胞假说表明,白血病克隆的起源和维持依赖于位于细胞层级顶端的一种罕见细胞群,这种细胞群具有无限的自我更新潜力,即白血病干细胞(LSCs)。异常激活的信号通路,包括GSK3-和Wnt/b-catenin通路,赋予MLL白血病细胞自我更新、增殖和抗凋亡特性。该项目的目标是表征原发性患者样本和具有良好特征的MLL白血病模型中LSC亚群的恶性/异常分层组织和信号传导特性。LSC频率和层次关系将在基线时动态跟踪,并响应MLL LSCs的药理信号和表观遗传靶向,使用大量细胞术(CYTOF)和异种移植模型。MLL白血病干细胞的表观遗传和信号靶向具有临床意义,并将允许开发临床疗法来根除该细胞亚群并改善MLL易位患者的预后。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Epigenetic Modifications Mediated by the AML1/ETO and MLL Leukemia Fusion Proteins
AML1/ETO 和 MLL 白血病融合蛋白介导的表观遗传修饰
- DOI:10.1007/978-3-642-38404-2_6
- 发表时间:2014
- 期刊:
- 影响因子:0
- 作者:Duque-Afonso J;Lübbert M;Cleary ML
- 通讯作者:Cleary ML
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Dr. Jesús Duque-Afonso其他文献
Dr. Jesús Duque-Afonso的其他文献
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{{ truncateString('Dr. Jesús Duque-Afonso', 18)}}的其他基金
Mechanisms of resistance to targeted therapy and chemotherapy in acute lymphoblastic leukemias
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423352691 - 财政年份:2019
- 资助金额:
-- - 项目类别:
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