The impact of AML - stromal cell interaction on malignant transformation, maintenance of leukemic stem cells and drug resistance

AML-基质细胞相互作用对恶性转化、白血病干细胞维持和耐药性的影响

• 批准号: 161794070
• 负责人: Professor Dr. Thomas Kindler
• 金额: --
• 依托单位: III. Medizinische Klinik und Poliklinik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/161794070?language=en
• 关键词: impact; AML; stromal; cell; interaction

Based on our current understanding of leukemogenesis, it is believed that the leukemic clone is perpetuated by a rare population of leukemia stem cells (LSC). These LSCs share many characteristics with normal hematopoietic stem cells (HSCs), such as phenotpype, self renewal potential, a quiescent cell cycle status and enhanced drug resistance. Whereas cytotoxic drugs eradicate actively cycling leukemic blasts, they often do not target LSCs, embed in their niche and protected against drug induced apoptotic cell death. Recent studies indicate, that the hematopoietic microenvironment or stem cell niche dictates stem cell quiescence, lack of motility and expression of anti-apoptotic proteins, which may result in refractory disease or relapse, a major concern in cancer therapy. Therefore, disruption of specific LSC – stroma cell interactions might drive this leukemia-maintaining cell population into cell cycle and make these cells vulnerable to chemotherapy. For this proposal, we already performed a global gene expression screen in stromal feeder layer cells upon co-culture with highly enriched LSCs or HSCs. Several interesting genes, such as receptor/ligands, extracellular matrix components or know oncogenes, were differentially regulated in stromal cells cultured with LSCs compared to HSCs. In this proposal, we will further analyse these genes in the context of LSCs – stromal cell interaction and functionally characterize the effect on LSC maintenance and development of drug resistance. Promising candidate genes will be further evaluated in murine in vivo models.

基于我们目前对白血病发生的理解，认为白血病克隆是由罕见的白血病干细胞（LSC）群体延续的。这些LSC与正常造血干细胞（HSC）有许多共同的特征，如表型，自我更新能力，静止细胞周期状态和增强的耐药性。尽管细胞毒性药物根除活跃循环的白血病母细胞，但它们通常不靶向LSC，嵌入其生态位并保护其免受药物诱导的凋亡性细胞死亡。最近的研究表明，造血微环境或干细胞生态位决定了干细胞静止、缺乏运动性和抗凋亡蛋白的表达，这可能导致难治性疾病或复发，这是癌症治疗中的主要问题。因此，特异性LSC -基质细胞相互作用的破坏可能驱使这种维持白血病的细胞群进入细胞周期，并使这些细胞对化疗敏感。对于该提议，我们已经在与高度富集的LSC或HSC共培养后的基质饲养层细胞中进行了全局基因表达筛选。几个有趣的基因，如受体/配体，细胞外基质成分或已知的癌基因，在与LSC培养的基质细胞与HSC相比，差异调节。在本提案中，我们将在LSC-基质细胞相互作用的背景下进一步分析这些基因，并在功能上表征对LSC维持和耐药性发展的影响。有希望的候选基因将在小鼠体内模型中进一步评估。