The p110 alpha and delta isoforms of PI3 kinase in hematopoiesis and leukemia

造血和白血病中 PI3 激酶的 p110 α 和 δ 亚型

基本信息

批准号：
8530989
负责人：
Kira Gritsman
金额：
$ 17.79万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8530989
关键词：
1-Phosphatidylinositol 3-Kinase Acute Myelocytic Leukemia Adult Affect Bone Marrow Bone Marrow Transplantation Catalytic Domain Cell physiology Cells Colony-Stimulating Factor Receptors Complement Data Disease Progression Disease model Embryo Epithelial Cells Erythropoiesis Erythropoietin Receptor Excision Failure G Protein-Coupled Receptor Signaling Genetic Goals Growth Growth Factor Hematopoiesis Hematopoietic Hematopoietic stem cells Human In Vitro Individual Knockout Mice Leukemic Cell Leukocytes MLL-AF9 Malignant Neoplasms Mediating Mediator of activation protein Modeling Mus Mutant Strains Mice Mutate Mutation Myeloproliferative disease Oncogenic Pathway interactions Patients Pharmaceutical Preparations Phosphatidylinositide 3-Kinase Inhibitor Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Process Protein Isoforms Protein Tyrosine Kinase Proto-Oncogene Protein c-kit Proto-Oncogene Proteins c-akt Receptor Protein-Tyrosine Kinases Receptor Signaling Role Sampling Signal Pathway Signal Transduction Solid Neoplasm System Therapeutic Toxic effect Tyrosine-Kinase Oncogenes Vascular Endothelial Growth Factor Receptor-1 base bcr-abl Fusion Proteins chemotherapy cytopenia design human PIK3CA protein inhibitor/antagonist insight leukemia leukemic stem cell leukemogenesis mortality novel outcome forecast public health relevance self-renewal therapeutic target tool tumor

项目摘要

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) affects 1 in 25,000 people per year, and is curable in only about 40% of cases. The mainstay of treatment is multi-agent chemotherapy and bone marrow transplantation, both of which have many complications and high mortality. This is largely attributed to the toxic effects that most antileukemic drugs have on hematopoietic stem cells (HSC), frequently leading to cytopenias. Therefore, it is crucial to determine which signaling pathways are important specifically in leukemic cells but not in HSCs, to enable the design of more specific and less toxic treatments for AML. The PI3 kinase (PI3K) pathway is pathologically activated in many human cancers, including AML. PI3K may also be important during hematopoiesis, as it is activated by hematopoietic growth factor receptors, such as erythropoietin receptor, c-kit receptor, and fms-like tyrosine kinase 3 (FLT3). In hematopoietic cells, receptor tyrosine kinases signal through the catalytic p110 subunit of PI3K, which has 3 isoforms (, , ), to activate the phosphorylation of the target kinase AKT. However, the roles of PI3K and its specific subunits in normal and leukemic stem cell function are poorly understood. We hypothesize that targeting individual subunits of PI3K may achieve the most selective anti-leukemic effect with minimal potential adverse affects. This proposal will utilize two novel genetic tools to investigate the roles of the PI3K subunits p110 and p110, individually and together, in leukemic cells and in normal HSCs: (1) mice with conditional deletion of p110 in hematopoietic cells and (2) double mutant mice with germline deletion of p110 and conditional deletion of p110. Preliminary data reveal that conditional deletion of p110 in HSCs results in impaired erythropoiesis, and slightly reduced HSC repopulating ability. As AKT signaling is maintained in p110-deleted bone marrow, we hypothesize that p110, a subunit expressed exclusively in hematopoietic cells, can complement for p110 in HSCs. In Specific Aim 1, we will analyze the effects of compound loss of p110 and p110 on HSC function and on AKT signaling in hematopoietic cells. Preliminary data suggests that deletion of p110 is insufficient to halt disease progression in at least some murine models of leukemia. Based on the failure of p110 excision to abrogate AKT signaling in hematopoietic cells, we hypothesize that it may be necessary to eliminate both p110 and p110 to inhibit the growth of leukemic cells. Specific Aim 2 will examine leukemia initiation and progression in mice after loss of p110, p110, or both using the bone marrow transplant system with retrovirally introduced mutated tyrosine kinases, including BCR-ABL, FLT3- ITD, and JAK2V617F. Specific Aim 3 will examine the roles of p110 and p110 in leukemic stem cell function in MLL-AF9-induced leukemia, which has been particularly difficult to target therapeutically. Together, these studies will provide important insights into the role and mechanism of PI3K signal transduction in HSCs, and the best strategies for therapeutic targeting of this pathway in leukemia. PUBLIC HEALTH RELEVANCE: PI3 kinase signaling is of central importance in solid tumors, but its roles in normal and leukemic stem cell function are poorly understood. This proposal will use mouse knockout models to examine whether the p110 and p110 subunits of PI3 kinase are important for normal HSC function and are feasible targets for leukemia therapy.

描述（由申请人提供）：每年每 25,000 人中就有 1 人患有急性髓性白血病 (AML)，并且只有约 40% 的病例可以治愈。主要治疗方法是多药化疗和骨髓移植，这两种方法并发症多，死亡率高。这主要归因于大多数抗白血病药物对造血干细胞（HSC）的毒性作用，常常导致血细胞减少。因此，确定哪些信号通路在白血病细胞中特别重要，但在造血干细胞中则不然，从而能够设计出更特异、毒性更小的 AML 治疗方法，这一点至关重要。 PI3 激酶 (PI3K) 通路在许多人类癌症（包括 AML）中被病理激活。 PI3K 在造血过程中也可能很重要，因为它被造血生长因子受体激活，例如促红细胞生成素受体、c-kit 受体和 fms 样酪氨酸激酶 3 (FLT3)。在造血细胞中，受体酪氨酸激酶通过 PI3K 的催化 p110 亚基（具有 3 个同种型 (, , )）发出信号，以激活靶激酶 AKT 的磷酸化。然而，人们对 PI3K 及其特定亚基在正常和白血病干细胞功能中的作用知之甚少。我们假设，针对 PI3K 的单个亚基可能会实现最具选择性的抗白血病作用，同时潜在的副作用最小。该提案将利用两种新颖的遗传工具来研究 PI3K 亚基 p110 和 p110 单独和共同在白血病细胞和正常 HSC 中的作用：（1）造血细胞中条件性删除 p110 的小鼠和（2）双突变体种系 p110 缺失和条件性 p110 缺失的小鼠。初步数据显示，HSC 中 p110 的条件性缺失会导致红细胞生成受损，并略微降低 HSC 的再增殖能力。由于 AKT 信号传导在 p110 缺失的骨髓中得以维持，因此我们假设 p110（一种仅在造血细胞中表达的亚基）可以补充 HSC 中的 p110。在具体目标 1 中，我们将分析 p110 和 p110 复合缺失对 HSC 功能和造血细胞中 AKT 信号传导的影响。初步数据表明，至少在某些小鼠白血病模型中，p110 的缺失不足以阻止疾病进展。基于 p110 切除未能消除造血细胞中的 AKT 信号传导，我们推测可能需要同时消除 p110 和 p110 来抑制白血病细胞的生长。具体目标 2 将使用骨髓移植系统和逆转录病毒导入突变酪氨酸激酶（包括 BCR-ABL、FLT3-ITD 和 JAK2V617F）检查小鼠 p110、p110 或两者缺失后白血病的发生和进展。具体目标 3 将检查 p110 和 p110 在 MLL-AF9 诱导的白血病中的白血病干细胞功能中的作用，这种白血病在治疗上特别困难。总之，这些研究将为了解 PI3K 信号转导在 HSC 中的作用和机制以及针对白血病中该通路的最佳治疗策略提供重要见解。公共健康相关性：PI3 激酶信号传导在实体瘤中至关重要，但其在正常和白血病干细胞功能中的作用却知之甚少。该提案将利用小鼠敲除模型来检验PI3激酶的p110和p110亚基是否对正常HSC功能很重要以及是否是白血病治疗的可行靶点。