Dissecting the Mechanism of Acute Myeloid Leukemia Induced Bone Marrow Failure to Identify Therapeutic Interventions

项目摘要/摘要 人急性髓系白血病(AML)是一种恶性血癌，死亡率高，预后差。 生存结果。大多数AML患者死于骨髓引起的并发症 导致造血细胞产量减少的衰竭。然而，我们缺乏基本的 关于驱动这一现象的机制的知识。 根据最近的数据显示，造血干和祖细胞几乎完全耗尽 在即使在低水平的疾病负担下也发生的人AML异种移植中的AML扩张期间， 拟议的工作将确定AML细胞的扩增是否取代了正常的干细胞和祖细胞 骨髓环境进入外周循环(目标1)，由此它们被困在 脾内皮细胞和血管周围壁龛。该项目还旨在表征脾内皮细胞 以及血管周围生态位，其细胞分类和能力仍未得到很好的定义 提供关键的利基因素(目标2)。这些研究将通过调查独特的 急性髓系白血病细胞产生的27-羟基胆固醇--氧固醇在正常造血失调中的作用 以旁分泌方式(目标3)。 这项工作将在遗传学专家Ravi Majeti博士的主要指导下进行 使用原代人急性髓系白血病异种移植的急性髓系白血病细胞的特性和治疗靶向。我的同事- 导师欧文·魏斯曼博士和中内弘博士都以他们的知识和 在骨髓和骨髓中的造血干和祖细胞的特征方面的专业知识 脾。这项工作将在斯坦福大学医学院进行世界级的研究 机构。拟议工作的结果有可能将现有的无毒和FDA 在一个非常难以治疗的疾病人群中，批准的药物进入早期临床试验。如果 资助，这个奖项将允许我在正常和恶性方面进行严格的培训计划 造血术，使我能够跨学科扩展我的研究，学习新技术，并获得 建立专注于骨髓逆转的独立实验室的知识和技能 AML失败。

PROJECT SUMMARY / ABSTRACT Human acute myeloid leukemia (AML) is an aggressive blood cancer with a high mortality rate and poor survival outcomes. The majority of AML patients die from complications arising from bone marrow failure which causes decreased production of blood forming cells. However, we lack fundamental knowledge regarding the mechanism driving this phenomenon. Building upon recent data which shows near complete depletion of hematopoietic stem and progenitors during AML expansion in human AML xenografts which occurred even with low level of disease burden, the proposed work will define whether AML cell expansion displaces normal stem and progenitors from the bone marrow environment into peripheral circulation (Aim 1) whereby they become entrapped in the splenic endothelial and perivascular niche. This project also aims to characterize the splenic endothelial and perivascular niche which remains poorly defined with respect to its cellular taxonomy and ability to provide critical niche factors (Aim 2). These studies will be complemented by investigating the unique oxysterol, 27-hydroxycholesterol, produced by AML cells in the dysregulation of normal hematopoiesis in a paracrine manner (Aim 3). This work will be performed under the primary mentorship of Dr. Ravi Majeti, an expert in the genetic characterization and therapeutic targeting of AML cells using primary human AML xenografts. My co- mentors, Dr. Irving Weissman and Dr. Hiro Nakauchi, are both renowned for their knowledge and expertise in the characterization of hematopoietic stem and progenitors cells in the bone marrow and spleen. This work will be conducted at Stanford University School of Medicine, a world-class research institution. The results of the proposed work have the potential to translate existing, non-toxic and FDA approved drugs into early phase clinical trials in a disease population that is very difficult to treat. If funded, this award will allow me to pursue a rigorous training plan in normal and malignant hematopoiesis, enabling me to expand my research across disciplines, learn new techniques, and acquire the knowledge and skills to establish an independent laboratory focused on the reversal of bone marrow failure in AML.