The role of the histone demethylase LSD1 in the pathogenesis of AML

组蛋白去甲基化酶LSD1在AML发病机制中的作用

• 批准号: 388039269
• 负责人: Professorin Dr. Heike L. Pahl
• 金额: --
• 依托单位: Sektion Molekulare Hämatologie
• 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/388039269?language=en
• 关键词: role; histone; demethylase; LSD1; pathogenesis

Despite novel therapeutic strategies, 50% of AML patients cannot achieve long-term remissions and succumb to their disease. The current model of AML pathogenesis proposes that a healthy hematopoietic stem cell (HSC) incurs several mutations to become a pre-leukemic stem cell (pre-LSC) and subsequently a leukemia initiating cell (LIC) from which the leukemic bulk cells evolve. Failure of our current therapies is attributed to eradication of the leukemic bulk but not the LICs. However, we lack knowledge of the changes that give rise to LICs and of their resistance mechanisms, both critical to achieving long-term remissions / functional cures. We have established a novel murine AML model by deletion of the lysine specific methylase LSD1 and subsequent bone marrow transplantation of LSD1 deficient cells. Single cell analyses from these mice define cells that represent healthy HSCs as well as all three aforementioned developmental stages of AML: pre-LSCs, LICs and an AML bulk. We propose to use data from these single cell analyses to determine the molecular changes that determine progression from HSC to pre-LSC and LIC as well as the differences between LICs and the leukemic bulk in LSD1 deficient AML.

尽管有新的治疗策略，50% 的 AML 患者仍无法实现长期缓解并死于疾病。目前的 AML 发病机制模型表明，健康的造血干细胞 (HSC) 会发生多种突变，成为白血病前干细胞 (pre-LSC)，随后成为白血病起始细胞 (LIC)，白血病细胞从该细胞进化而来。我们当前疗法的失败归因于白血病群体的根除，但 LIC 并未根除。然而，我们缺乏对引起 LIC 的变化及其耐药机制的了解，而这两者对于实现长期缓解/功能性治愈都至关重要。我们通过删除赖氨酸特异性甲基化酶 LSD1 并随后对 LSD1 缺陷细胞进行骨髓移植，建立了一种新型小鼠 AML 模型。对这些小鼠的单细胞分析确定了代表健康 HSC 以及上述所有三个 AML 发育阶段的细胞：前 LSC、LIC 和 AML 体。我们建议使用这些单细胞分析的数据来确定决定从 HSC 进展到前 LSC 和 LIC 的分子变化，以及 LIC 与 LSD1 缺陷 AML 中白血病细胞之间的差异。