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

• 批准号: 9103377
• 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
• 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/9103377
• 关键词: 1-Phosphatidylinositol 3-Kinase; AML1-ETO fusion protein; Ablation; Acute Myelocytic Leukemia; Address; Adult; Affect; Apoptosis; Bone Marrow Transplantation; Catalytic Domain; Cell Cycle; Cell Line; Cell physiology; Cells; Clinic; Clinical; Data; Dependence; Development; Diagnosis; Disease; Disease remission; Dose; Epigenetic Process; Gene Targeting; Genes; Genetic; Genomics; Goals; Growth; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Human; 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; Phosphatidylinositide 3-Kinase Inhibitor; Phosphorylation; Phosphotransferases; Population; Protein Biosynthesis; Protein Isoforms; Protein Kinase; Receptor Protein-Tyrosine Kinases; Relapse; Reporting; Resistance; Role; Safety; Sampling; Selection Criteria; Series; Signal Transduction; Specificity; Survival Rate; Therapeutic; Toxic effect; Xenograft procedure; cancer cell; chemokine; chemotherapy; 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

 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（由申请人提供）：急性髓性白血病（AML）是一种毁灭性的疾病，每年约有19，000人被诊断出，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，两者都与高发病率和死亡率相关，主要是由于对造血干细胞（HSC）的毒性作用。为了能够设计更特异性的AML治疗方法，关键是要确定白血病起始细胞（LIC）中的治疗靶点，因为该细胞群在AML治疗中很重要。 复发和抵抗。PI3激酶（PI3K）是一种脂质和蛋白激酶，其转导生长因子和趋化因子信号，导致Ser/Thr激酶Akt的磷酸化和活化，其调节代谢、细胞周期、凋亡和蛋白质合成。在AML患者样本中经常报告Akt的病理性磷酸化，并且在AML细胞系、患者样本和小鼠白血病模型中已经显示了对PI3K/Akt通路的抑制的功效。该通路是白血病和其他恶性肿瘤的有吸引力的治疗靶点。然而，PI3K信号在正常成体HSC中的作用尚不清楚。这是PI3K/Akt抑制剂在临床中潜在毒性的重要考虑因素。在造血干细胞中，表达了编码PI3K催化亚基的四种不同亚型（p110酪氨酸激酶抑制剂和酪氨酸激酶抑制剂）的基因。这些亚型在正常细胞和癌细胞中具有独特的功能，但在某些情况下可能相互替代。目前有两类PI3K抑制剂处于临床开发中：靶向所有四种PI3K亚型的泛PI3K抑制剂和仅有利于一种或两种亚型的亚型选择性抑制剂。为了确定哪些PI3K同种型对于造血是必需的，以及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种型单独在成人HSC中的作用。我们最近发现，RAS突变的骨髓白血病依赖于PI 3 K的p110 alpha亚型，并且p110 alpha的药理学抑制在治疗RAS突变白血病的小鼠模型中有效。然而，在p110 α缺失的情况下，正常的HSC功能得以维持，使其成为安全的治疗靶点。目前尚不清楚PI3K是否是成体HSC功能所必需的，因为其他PI3K亚型可能会补偿HSC中的p110 α。此外，PI3K在LIC中的作用尚不清楚。我们现在已经产生了新的化合物敲除小鼠模型，这将使诱导条件下删除多种PI3K亚型在成年HSC。在具体目标1中，我们将进一步表征PI3K亚型在HSC功能、自我更新、增殖和分化中的冗余作用。在具体目标2中，我们将在AML小鼠模型中基因消除PI3K亚型，以确定PI3K在LIC功能中的作用。目前，尚未建立选择最有可能对亚型选择性PI3K抑制剂治疗有反应的AML患者的标准。为了解决这个问题，在具体目标3中，我们将描述AML中PI3K依赖性和PI3K亚型特异性的分子决定因素。