PI3 Kinase Inactivation in Myelodysplastic Syndrome

骨髓增生异常综合征中的 PI3 激酶失活

基本信息

批准号：
10669279
负责人：
Kira Gritsman
金额：
$ 55.9万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10669279
关键词：
Abnormal Cell Affect Alternative Splicing Animal Model Arginine Autophagocytosis Biological Models Cells Clinical Cytokine Signaling DNA Damage Data Data Set Defect Dependence Development Disease Dysmyelopoietic Syndromes Dysplasia Event Exons Gene Expression Gene Expression Profile Genes Genomic Instability Growth Factor Hematopoiesis Hematopoietic Hematopoietic Cell Growth Factors Hematopoietic stem cells Hemorrhage Human Impairment Infection Knock-out Knockout Mice Lead Link Lipids Maintenance Messenger RNA Metformin Modeling Mus Mutation Myelogenous Nuclear PIK3CG gene PTEN gene Pathogenesis Pathway interactions Patients Pattern Persons Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Play Process Protein Isoforms Protein Kinase Proteins Proto-Oncogene Proteins c-akt Quality Control RNA Splicing RNA-Binding Proteins Recycling Reporting Role Sampling Serine Signal Transduction Spliceosomes Testing Therapeutic Transfusion aging population biological adaptation to stress cytopenia drug candidate erythroid differentiation exon skipping hematopoietic stem cell differentiation improved inhibitor mortality mouse model mutant novel therapeutic intervention pharmacologic prevent public health relevance stem cell biology stem cell function stem cell genes stem cells therapeutic target

项目摘要

Myelodysplastic Syndrome (MDS) affects at least 10,000 people each year in the U.S., and is particularly prevalent in the aging population. MDS is a clonal disorder arising in hematopoietic stem cells (HSCs), characterized by impaired myeloid and erythroid differentiation and genomic instability. There are currently few therapeutic approaches available to improve cytopenias in MDS patients. Mutations in RNA splicing factors are observed in 50% of MDS cases, and are important contributors to MDS initiation and progression. Most hematopoietic growth factors and cytokines signal through the PI3 kinase (PI3K)/AKT pathway. We have found that compound deletion of the three PI3K isoforms P110a, b, and d in mouse hematopoietic cells leads to a phenotype resembling MDS, with cytopenias, impaired HSC differentiation and genomic instability. Interestingly, we observed enrichment of our TKO HSC expression signature in an MDS patient gene expression dataset. Furthermore, a subset of MDS samples have elevated expression levels of the negative regulator PTEN, suggesting functional inactivation of PI3K in these MDS patients. Our preliminary data reveals that HSCs in PI3K triple knockout (TKO) mice have a defect in autophagy, an intracellular recycling mechanism that is important for the maintenance of HSC differentiation. We found that pharmacologic induction of autophagy can improve differentiation of TKO HSCs. We also observed widespread alterations in mRNA splicing in TKO HSCs. Therefore, PI3K TKO mice are a valuable new model system to study the mechanisms of MDS initiation and progression. We hypothesize that maintenance of PI3K signaling in HSCs is required to maintain HSC differentiation and to protect HSCs from DNA damage. We propose to (1) determine whether induction of autophagy can improve myeloid and erythroid differentiation in MDS patient samples, (2) delineate the mechanism by which PI3K and its downstream kinase AKT control mRNA splicing in HSCs and in MDS, and (3) determine whether MDS cells with splicing factor mutations are more sensitive to inhibition of PI3K/AKT signaling. These approaches will further our understanding of how growth factor and cytokine signaling regulates autophagy and mRNA splicing through PI3K/AKT in MDS initiation. We also plan to test several therapeutic approaches to improve differentiation in MDS, including induction of autophagy and inhibition of PI3K/AKT in MDS with splicing factor mutations.

骨髓增生综合征（MDS）在美国每年至少影响10,000人，并且在老龄化人群中尤为普遍。 MDS是一种在造血干细胞（HSC）中产生的克隆疾病，其特征是髓样和红细胞分化和基因组不稳定性受损。目前，几乎没有可用的治疗方法可以改善MDS患者的细胞质减少症。 RNA剪接因子中的突变是在50％的MDS病例中观察到，这是MDS启动和进展的重要贡献者。大多数造血生长因子和细胞因子通过PI3激酶（PI3K）/AKT途径信号。我们发现，小鼠造血细胞中三个PI3K同工型P110A，B和D的复合缺失导致类似于MDS的表型，具有细胞质，HSC分化受损和基因组不稳定性。有趣的是，我们观察到MDS患者基因表达数据集中的TKO HSC表达特征的富集。此外，MDS样品的一个子集具有负调节剂PTEN的表达水平升高，表明这些MDS患者PI3K的功能失活。我们的初步数据表明，PI3K三重敲除（TKO）小鼠中的HSC具有自噬的缺陷，自噬是一种细胞内回收机制，对于维持HSC分化很重要。我们发现自噬的药理学诱导可以改善TKO HSC的分化。我们还观察到TKO HSC中mRNA剪接的广泛改变。因此，PI3K TKO小鼠是研究MDS启动和进展机制的宝贵新模型系统。我们假设HSC中PI3K信号的维护为需要维持HSC分化并保护HSC免受DNA损伤。 We propose to (1) determine whether induction of autophagy can improve myeloid and erythroid differentiation in MDS patient samples, (2) delineate the mechanism by which PI3K and its downstream kinase AKT control mRNA splicing in HSCs and in MDS, and (3) determine whether MDS cells with splicing factor mutations are more sensitive to inhibition of PI3K/AKT signaling.这些方法将进一步了解生长因子和细胞因子信号如何通过MDS启动中PI3K/AKT调节自噬和mRNA剪接。我们还计划测试几种治疗方法，以改善MDS的分化，包括诱导具有剪接因子突变的MDS中PI3K/AKT的自噬和抑制。