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：
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
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/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

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（由申请人提供）：急性髓性白血病 (AML) 是一种毁灭性疾病，每年约有 19,000 人被诊断出来，5 年生存率仅为 24%。主要治疗方法是多药化疗和骨髓治疗。移植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。对于确定白血病起始细胞 (LIC) 的治疗靶点至关重要，因为该细胞群在 PI3 激酶 (PI3K) 是一种脂质和蛋白激酶，可转导生长因子和趋化因子信号，导致 Ser/Thr 激酶 Akt 磷酸化和激活，从而调节代谢、细胞周期、细胞凋亡和蛋白质合成。 Akt 的病理磷酸化在 AML 患者样本中经常被报道，并且 PI3K/Akt 通路的抑制已在 AML 细胞系、患者样本和小鼠白血病模型中显示出功效。是白血病和其他恶性肿瘤的一个有吸引力的治疗靶标，然而，PI3K 信号在正常成人 HSC 中的作用尚不清楚，这是 PI3K/Akt 抑制剂在造血细胞中潜在毒性的一个重要考虑因素。 PI3K 催化亚基的不同异构体 (p110  和这些异构体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会相互替代。目前正在临床开发中的有两类 PI3K 抑制剂：针对所有四种 PI3K 异构体的泛 PI3K 抑制剂。同工型选择性抑制剂，仅支持一种或两种同工型确定哪些 PI3K 同工型对于造血至关重要，哪些更重要。在白血病细胞中，我们生成了一系列小鼠敲除模型，以研究每种异构体在成人 HSC 中的作用，我们最近发现 RAS 突变的髓系白血病依赖于 PI3K 的 p110α 异构体，并且 p110α 的药理学抑制是有效的。然而，在缺乏 p110α 的情况下，正常的 HSC 功能仍能维持，这使其成为一种治疗 RAS 突变白血病的小鼠模型。目前尚不清楚 PI3K 是否对成人 HSC 功能至关重要，因为其他 PI3K 亚型可能会补偿 HSC 中的 p110α。此外，我们现在还不清楚 PI3K 在 LIC 中的作用。这将使成体 HSC 中多个 PI3K 同工型的诱导条件删除成为可能。在具体目标 1 中，我们将进一步表征 PI3K 的冗余作用。 PI3K 同工型在 HSC 功能、自我更新、增殖和分化中的作用在特定目标 2 中，我们将在 AML 小鼠模型中对 PI3K 同工型进行基因消除，以确定 PI3K 在 LIC 功能中的作用。尚未确定最有可能对异构体选择性 PI3K 抑制剂治疗产生反应的 AML 患者。为了解决这个问题，我们在具体目标 3 中进行了研究。将描述 AML 中 PI3K 依赖性和 PI3K 亚型特异性的分子决定因素。