PI3K Isoform Dependence in Adult Hematopoiesis and Myeloid Leukemia

成人造血和髓性白血病中 PI3K 同工型依赖性

基本信息

批准号：
9251260
负责人：
Kira Gritsman
金额：
$ 40.92万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9251260
关键词：
1-Phosphatidylinositol 3-Kinase AML1-ETO fusion protein Ablation Acute Myelocytic Leukemia Address Adult Apoptosis Bone Marrow Transplantation Catalytic Domain Cell Cycle Cell Line Cell physiology Cells Clinic Clinical Data Dependence Diagnosis Disease Disease remission Dose Epigenetic Process Gene Targeting Genes Genetic Genomics Goals Growth Factor Hematopoiesis Hematopoietic Hematopoietic System Hematopoietic stem cells Human Impairment In Vitro Individual Knockout Mice Leukemic Cell Lipids MLL-AF9 Maintenance Malignant Neoplasms Metabolism Modeling Molecular Morbidity - disease rate Mus Mutate Mutation Myeloid Leukemia Normal Cell Outcome Pathogenesis Pathologic Pathway interactions Patients Pharmacology Phosphatidylinositide 3-Kinase Inhibitor Phosphorylation Phosphotransferases Population Protein Biosynthesis Protein Isoforms Protein Kinase Receptor Protein-Tyrosine Kinases Receptor Signaling Relapse Reporting Resistance Role Safety Sampling Selection Criteria Series Signal Pathway Signal Transduction Specificity Survival Rate Therapeutic Toxic effect Xenograft procedure cancer cell chemokine chemotherapy clinical development design effective therapy in vivo inhibitor/antagonist leukemia leukemia treatment leukemic stem cell molecular subtypes mortality mouse model novel prevent progenitor public health relevance self-renewal targeted treatment therapeutic target

1-Phosphatidylinositol 3-Kinase AML1-ETO fusion protein Ablation Acute Myelocytic Leukemia Address Adult Apoptosis Bone Marrow Transplantation Catalytic Domain Cell Cycle Cell Line Cell physiology Cells Clinic Clinical Data Dependence Diagnosis Disease Disease remission Dose Epigenetic Process Gene Targeting Genes Genetic Genomics Goals Growth Factor Hematopoiesis Hematopoietic Hematopoietic System Hematopoietic stem cells Human Impairment In Vitro Individual Knockout Mice Leukemic Cell Lipids MLL-AF9 Maintenance Malignant Neoplasms Metabolism Modeling Molecular Morbidity - disease rate Mus Mutate Mutation Myeloid Leukemia Normal Cell Outcome Pathogenesis Pathologic Pathway interactions Patients Pharmacology Phosphatidylinositide 3-Kinase Inhibitor Phosphorylation Phosphotransferases Population Protein Biosynthesis Protein Isoforms Protein Kinase Receptor Protein-Tyrosine Kinases Receptor Signaling Relapse Reporting Resistance Role Safety Sampling Selection Criteria Series Signal Pathway Signal Transduction Specificity Survival Rate Therapeutic Toxic effect Xenograft procedure cancer cell chemokine chemotherapy clinical development design effective therapy in vivo inhibitor/antagonist leukemia leukemia treatment leukemic stem cell molecular subtypes mortality mouse model novel prevent progenitor public health relevance self-renewal targeted treatment therapeutic target

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项目摘要

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is a devastating disease that is diagnosed in about 19,000 people per year, with a 5-year survival of only 24%. The mainstay of treatment is multi-agent chemotherapy and bone marrow transplantation, both associated with high morbidity and mortality, largely due to toxic effects on hematopoietic stem cells (HSC). To enable the design of more specific treatments for AML, it is critical to identify therapeutic targets in leukemia-initiating cells (LICs), since this cell population is important in relapse and resistance. PI3 kinase (PI3K) is a lipid and protein kinase that transduces growth factor and chemokine signals, leading to phosphorylation and activation of the Ser/Thr kinase Akt, which regulates metabolism, the cell cycle, apoptosis, and protein synthesis. Pathologic phosphorylation of Akt is frequently reported in AML patient samples, and inhibition of the PI3K/Akt pathway has shown efficacy in AML cell lines, patient samples, and mouse leukemia models. This pathway is an attractive therapeutic target for leukemia and other malignancies. However, the role of PI3K signaling in normal adult HSCs is unclear. This is an important consideration for the potential toxicity of PI3K/Akt inhibitors in the clinic. In hematopoietic cels, genes encoding four different isoforms of the catalytic subunit of PI3K (p110  and ) are expressed. These isoforms have unique functions in normal and cancer cells, but may substitute for each other in some contexts. Two classes of PI3K inhibitors are currently in clinical development: pan-PI3K inhibitors, which target all four PI3K isoforms, and isoform-selective inhibitors, which favor only one or two isoforms. To determine which of the PI3K isoforms are essential for hematopoiesis, and which are more important in leukemic cells, we have generated a series of mouse knockouts to study the roles of each isoform individually in adult HSCs. We recently found that RAS- mutated myeloid leukemias are dependent on the p110alpha isoform of PI3K, and that pharmacologic inhibition of p110alpha is effective in treatment of murine models of RAS-mutated leukemia. However, normal HSC functions are maintained in the absence of p110alpha, making it a safe therapeutic target. It is still not known whether PI3K is essential for adult HSC function, as other PI3K isoforms may compensate for p110alpha in HSCs. Furthermore, the role of PI3K in LICs is unclear. We have now generated novel compound knockout mouse models, which will enable the inducible conditional deletion of multiple PI3K isoforms in adult HSCs. In Specific Aim 1, we will further characterize the redundant roles of the PI3K isoforms in HSC function, self-renewal, proliferation, and differentiation. In Specific Aim 2, we will genetically ablate PI3K isoforms in mouse models of AML, in order to determine the roles of PI3K in LIC function. At the moment, criteria for the selection of AML patients that are most likely to respond to isoform-selective PI3K inhibitor treatment have not been established. To address this issue, in Specific Aim 3, we will delineate the molecular determinants for PI3K dependence and PI3K isoform specificity in AML.

描述（由适用提供）：急性髓细胞性白血病（AML）是一种毁灭性疾病，每年约有19,000人被诊断出，仅5年生存率仅为24％。治疗的主要手段是多药化疗和骨髓移植，既与高发病率和死亡率有关，这主要是由于对造血干细胞（HSC）的毒性作用。为了实现AML的更具体处理的设计，确定白血病发射细胞（LIC）中的治疗靶标至关重要，因为该细胞群在复发和抵抗。 PI3激酶（PI3K）是一种脂质和蛋白激酶，可转化生长因子和趋化因子信号，导致Ser/Thr激酶Akt的磷酸化和激活，可调节代谢，细胞周期，凋亡和蛋白质合成。 AKT的病理磷酸化经常在AML患者样品中报道，抑制PI3K/AKT途径在AML细胞系，患者样品和小鼠白血病模型中表现出效率。该途径是白血病和其他恶性肿瘤的有吸引力的治疗靶标。但是，PI3K信号在正常成年HSC中的作用尚不清楚。这是诊所中PI3K/AKT抑制剂的潜在毒性的重要考虑因素。在造血片中，表达了编码PI3K催化亚基的四种不同同工型（P110和）的基因。这些同工型在正常和癌细胞中具有独特的功能，但在某些情况下可能会互相代替。目前有两类的PI3K抑制剂正在临床开发中：PAN-PI3K抑制剂，它们针对所有四种PI3K同工型和同工型选择抑制剂，仅有利于一两个同工型。为了确定哪种PI3K同工型对于造血是必不可少的，哪些在白血病细胞中更重要，我们已经产生了一系列小鼠敲除，以研究每个同工型在成人HSC中的作用。最近，我们发现，ras突变的髓样白血病取决于PI3K的P110Alpha同工型，并且P110Alpha的药理学抑制有效地治疗了RAS突变白血病的鼠模型。但是，在没有p110alpha的情况下，保持正常的HSC功能，使其成为安全的治疗靶标。尚不清楚PI3K是否对于成人HSC功能至关重要，因为其他PI3K同工型可能会补偿HSC中的P110Alpha。此外，PI3K在LIC中的作用尚不清楚。现在，我们已经生成了新型的复合基因敲除小鼠模型，这将使成人HSC中多种PI3K同工型的诱导条件缺失。在特定目标1中，我们将进一步表征PI3K同工型在HSC功能，自我更新，增殖和分化中的冗余作用。具体的目标2，我们将通常在AML的鼠标模型中烧蚀PI3K同工型，以确定PI3K在LIC函数中的作用。目前，尚未确定选择最有可能对同工型选择PI3K抑制剂治疗反应的AML患者的标准。为了解决这个问题，在特定的目标3中，我们将描述AML中PI3K依赖性和PI3K同工型特异性的分子决定剂。