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

项目总结/摘要 人类急性髓细胞白血病（AML）是一种侵袭性血液癌症，具有高死亡率和低预后。 生存结果。大多数AML患者死于骨髓炎引起的并发症。 导致造血细胞生成减少的衰竭。然而，我们缺乏基本的 了解驱动这种现象的机制。 基于最近的数据显示造血干细胞和祖细胞几乎完全耗尽， 在人AML异种移植物中的AML扩增期间（即使在低水平疾病负荷下也发生）， 拟议的工作将确定AML细胞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（Aim 1），从而它们被截留在 脾内皮和血管周围小生境。该项目还旨在表征脾内皮细胞 和血管周围生态位，其在细胞分类学和 提供关键的利基因素（目标2）。这些研究将通过调查独特的 氧化固醇，27-羟基胆固醇，由AML细胞在正常造血功能失调中产生 以旁分泌的方式（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AML异种移植物的AML细胞的表征和治疗靶向。我的同事 导师欧文·韦斯曼博士和中内弘博士都以他们的知识和 在骨髓中造血干细胞和祖细胞表征方面的专业知识， 脾脏这项工作将在斯坦福大学医学院进行，一项世界级的研究 机构。拟议工作的结果有可能将现有的、无毒的和FDA 在很难治疗的疾病人群中进行早期临床试验。如果 资助，这个奖项将使我能够追求一个严格的培训计划，在正常和恶性 造血，使我能够扩大我的跨学科研究，学习新技术，并获得 知识和技能，建立一个独立的实验室，专注于骨髓逆转 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.