Deregulation of Ras Signaling in MLL-Induced Leukemia

MLL 诱导的白血病中 Ras 信号传导的失调

• 批准号: 7079568
• 负责人: MICHAELA LIEDTKE
• 金额: $ 13.81万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7079568
• 关键词: carcinogenesis; human; leukemia; model; proteins

DESCRIPTION (provided by applicant): The objective of this 5-year proposal is to provide the applicant with an integrated research training and mentoring program that will ensure her successful development as an independent physician scientist. We propose to investigate the mechanisms and develop model systems of transformation by a subset of mixed lineage leukemia (MLL) oncoproteins that may share dual roles to simultaneously activate Ras signaling and MLL transcriptional pathways. The histone methyltransferase MLL is a transcriptional regulator essential for embryonal hematopoiesis, and is frequently fused to various partner proteins in infant and secondary leukemia. The transforming ability of MLL fusion proteins is thought to be caused by aberrant transcriptional effector properties conferred by the fusion partner, but the exact mechanisms are poorly understood. We have identified the Ras association 1 domain of the MLL fusion partner AF6 as critical for activation of the oncogenic properties of MLL linking MLL-induced leukemogenesis to Ras. Also, it was recently found that due to fusion with MLL, cytoplasmic EEN and its interaction partner EEN binding protein (EBP) are abducted to the nucleus. As a result EBP no longer exerts its inhibitory function on the Ras pathway. Similarly, fusion of RASGAP to MLL results in sequestration of RASGAP in the nucleus and interferes with its ability to inhibit Ras. We hypothesize that transformation by MLL-AF6, MLL-EEN and MLL-RASGAP is in part mediated by activation of Ras and that inhibition of the Ras pathway is a suitable treatment approach for leukemias induced by these MLL-fusion proteins. To test this hypothesis, we propose the following specific aims. 1. Investigate the molecular mechanisms by which fusion with AF6, RASGAP and EEN activate the oncogenic potential of MLL. 2. Assess potential deregulation of the Ras pathway by the respective MLL fusion protein and investigate the effect of Ras pathway inhibition on their transforming ability in vitro. 3a) Establish a murine xenograft of MLL-AF6, MLL-EEN and MLL-RASGAP-induced leukemia using human cord blood cells transduced with the respective MLL fusion protein. 3b) Assess the efficacy of Ras-pathway inhibitors in the xenograft model for treatment of leukemia induced by MLL-AF6, MLL-EEN and MLL-RASGAP. These studies will lead to a better understanding of the molecular mechanisms of leukemogenesis mediated by a subset of MLL fusion proteins and may facilitate the development and testing of novel targeted therapies.

描述（由申请人提供）：本5年提案的目标是为申请人提供综合研究培训和指导计划，以确保她成功发展为独立的医生科学家。我们建议调查的机制，并开发模型系统的转换由一个子集的混合谱系白血病（MLL）癌蛋白，可能共享双重角色，同时激活Ras信号和MLL转录途径。组蛋白甲基转移酶MLL是胚胎造血所必需的转录调节因子，并且在婴儿和继发性白血病中经常与各种伴侣蛋白融合。MLL融合蛋白的转化能力被认为是由融合伴侣赋予的异常转录效应子特性引起的，但确切的机制知之甚少。我们已经确定MLL融合伴侣AF 6的Ras相关1结构域对于激活MLL的致癌特性至关重要，其将MLL诱导的白血病发生与Ras联系起来。此外，最近发现，由于与MLL融合，胞质EEN及其相互作用伴侣EEN结合蛋白（EBP）被绑架到细胞核。因此，EBP不再对Ras通路发挥其抑制功能。类似地，RASGAP与MLL的融合导致RASGAP在核中的隔离并干扰其抑制Ras的能力。我们假设MLL-AF 6、MLL-EEN和MLL-RASGAP的转化部分是由Ras的活化介导的，并且Ras途径的抑制是由这些ML融合蛋白诱导的白血病的合适的治疗方法。为了验证这一假设，我们提出了以下具体目标。 1.研究与AF 6、RASGAP和EEN融合激活MLL致癌潜力的分子机制。 2.评估各MLL融合蛋白对Ras途径的潜在失调，并研究Ras途径抑制对其体外转化能力的影响。 3a）使用用相应MLL融合蛋白转导的人脐带血细胞建立MLL-AF 6、MLL-EEN和MLL-RASGAP诱导的白血病的鼠异种移植物。 3b）评估Ras途径抑制剂在异种移植模型中治疗由MLL-AF 6、MLL-EEN和MLL-RASGAP诱导的白血病的功效。这些研究将导致更好地了解白血病的分子机制介导的MLL融合蛋白的一个子集，并可能促进新的靶向治疗的开发和测试。