The role of Pleckstrin-2 as a functional node in myeloid proliferation

Pleckstrin-2 作为功能节点在骨髓增殖中的作用

• 批准号: 10650349
• 负责人: Peng Ji
• 金额: $ 48.68万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-09 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650349
• 关键词: Acute Myelocytic Leukemia; Anemia; Binding; Binding Proteins; Biochemical; Biological Assay; Blood Cell Count; Blood Cells; Blood Vessels; Blood coagulation; Bone Marrow Diseases; Bone Marrow Transplantation; Cells; Clinical Trials; Complex; Data; Development; Drug resistance; Erythropoietin; FDA approved; Foundations; Funding; Future; Goals; Hematopoiesis; Hematopoietic; Hemorrhagic Thrombocythemia; In Vitro; Infiltration; Injections; JAK2 gene; Knock-in; Knock-in Mouse; Knock-out; Knockout Mice; Lead; Membrane; Modeling; Molecular; Mus; Mutation; Myelogenous; Myeloid Cells; Myeloproliferation; Myeloproliferative disease; Names; Neutrophilia; PIK3CG gene; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Chemistry; Phenotype; Philadelphia Chromosome; Phosphatidylinositols; Phosphorylation; Polycythemia Vera; Primary Myelofibrosis; Production; Proliferating; Protein Dephosphorylation; Publishing; Reticulocytosis; Risk; Role; Sampling; Scaffolding Protein; Signal Transduction; Spleen; Splenomegaly; Stat5 protein; Testing; Therapeutic; Thrombocytopenia; Thrombosis; Toxic effect; Work; driver mutation; drug resistance development; effective therapy; genetic approach; high throughput screening; in silico; in vivo; in vivo Model; inhibitor; insight; mouse genetics; mouse model; new therapeutic target; novel; novel strategies; novel therapeutic intervention; overexpression; phosphatidylinositol 3,4,5-triphosphate; platelet protein P47; pre-clinical; recruit; side effect; small molecule inhibitor; thrombocytosis; transplant model

PROJECT SUMMARY Myeloproliferative neoplasms (MPNs) are a group of bone marrow diseases that show excessive myeloid cell production with an increased risk of developing thrombosis and evolving to acute myeloid leukemia. V617F driver mutation of JAK2 is one of the leading causes of MPNs. The discovery of this mutation led to the development of JAK inhibitors to treat MPNs. However, JAK inhibitors are not curative. In addition, MPN patients treated with JAK inhibitor often develop drug resistance and severe side effects due to the indispensable roles of JAK2 in normal hematopoiesis. We have been studying new approaches to treat MPNs, especially focusing on the downstream effectors of the JAK2 pathway. Our recently published studies funded by the current R01 revealed that loss of Pleckstrin-2 (Plek2), a novel target of the JAK2-STAT5 pathway, ameliorated JAK2V617F-induced myeloproliferative phenotypes, and more importantly reverted vascular occlusions and lethality of the JAK2V617F MPN mouse model. Given the significance of Plek2 in MPN pathogenesis, we have identified lead compounds of Plek2 small molecule inhibitors using in silico-based high- throughput screenings and cell-based assays. Our novel unpublished preliminary data further reveal that Plek2 binds to several PI3K effectors and loss of Plek2 reduces Akt activation. Preliminary in vivo evidence also demonstrates that Plek2 is critical for the PI3K-Akt pathway in that Plek2 knockout ameliorated myeloproliferation and significantly extended the survival of Pten hematopoietic specific knockout mice. These findings lead us to hypothesize that Plek2 functions as a central hub to connect the JAK2-STAT and the PI3K- Akt pathways and promote myeloproliferation. To test this hypothesis and investigate the mechanism of function of Plek2, we will use 1) in vitro biochemical and molecular studies to determine how Plek2 enhances the PI3K-Akt signaling, 2) Pten hematopoietic specific knockout mouse model to reveal the functions of Plek2 in vivo, and 3) pre-clinical MPN models and MPN patient samples to establish the efficacy of Plek2 inhibitors. Successful completion of this project will lead to novel insights into the role of Plek2 in the pathogenesis of MPNs and lay the foundation for clinical trials using Plek2 inhibitors as single agents or in combination with other compounds to treat MPNs.

项目概要 骨髓增生性肿瘤（MPN）是一组表现为骨髓细胞过多的骨髓疾病 产生血栓并发展为急性髓性白血病的风险增加。 V617F JAK2 驱动突变是 MPN 的主要原因之一。这种突变的发现导致 开发 JAK 抑制剂来治疗 MPN。然而，JAK 抑制剂没有治疗作用。此外，MPN 使用 JAK 抑制剂治疗的患者经常会出现耐药性和严重的副作用，因为 JAK2 在正常造血过程中发挥着不可或缺的作用。我们一直在研究治疗 MPN 的新方法， 特别关注 JAK2 通路的下游效应器。我们最近发表的研究资助 当前的 R01 揭示了 JAK2-STAT5 途径的新靶点 Pleckstrin-2 (Plek2) 的丢失， 改善 JAK2V617F 诱导的骨髓增殖表型，更重要的是恢复血管 JAK2V617F MPN 小鼠模型的闭塞和致死率。鉴于 Plek2 在 MPN 中的重要性 发病机制，我们已经确定了 Plek2 小分子抑制剂的先导化合物，用于基于硅基的高 通量筛选和基于细胞的测定。我们未发表的小说初步数据进一步表明 Plek2 与多个 PI3K 效应子结合，Plek2 的缺失会降低 Akt 激活。初步的体内证据也 表明 Plek2 对于 PI3K-Akt 通路至关重要，因为 Plek2 敲除可改善 骨髓增殖并显着延长 Pten 造血特异性敲除小鼠的生存期。这些 研究结果使我们假设 Plek2 充当连接 JAK2-STAT 和 PI3K- 的中央枢纽。 Akt 通路并促进骨髓增殖。为了检验这一假设并研究其机制 Plek2 的功能，我们将使用 1) 体外生化和分子研究来确定 Plek2 如何增强 PI3K-Akt 信号转导，2) Pten 造血特异性敲除小鼠模型揭示 Plek2 的功能 体内，3) 临床前 MPN 模型和 MPN 患者样本，以确定 Plek2 抑制剂的功效。 该项目的成功完成将为 Plek2 在疾病发病机制中的作用提供新的见解 MPN 并为使用 Plek2 抑制剂作为单药或联合用药的临床试验奠定基础 其他治疗 MPN 的化合物。

项目成果

The inner nuclear membrane protein NEMP1 is required for nuclear envelope 1 openings and enucleation of erythroblasts during erythropoiesis supports nuclear envelope openings of erythroblasts

内核膜蛋白 NEMP1 是红细胞生成过程中核膜 1 开口和红细胞去核所必需的，支持红细胞的核膜开口

• 发表时间: 2024-09-13
• 作者: D. Hodzic;Jun Wu;Karen Krchma;A. Jurisicova;Y. Tsatskis;Yijie;Liu;P. Ji;Kyunghee Choi
• 通讯作者: Kyunghee Choi

Bone-derived C-terminal FGF23 cleaved peptides increase iron availability in acute inflammation.

骨源性 C 末端 FGF23 裂解肽可增加急性炎症中铁的利用率。

• 发表时间: 2023-07-06
• 影响因子: 20.3
• 作者: Courbon, Guillaume;Thomas, Jane Joy;Martinez;Wang, Xueyan;Spindler, Jadeah;Von Drasek, John;Hunt;Mehta, Rupal;Isakova, Tamara;Chang, Wenhan;Creemers, John W M;Ji, Peng;Martin, Aline;David, Valentin
• 通讯作者: David, Valentin

Membrane skeleton modulates erythroid proteome remodeling and organelle clearance.

膜骨架调节红细胞蛋白质组重塑和细胞器清除。

• DOI: 10.1182/blood.2020006673
• 发表时间: 2020-10-09
• 期刊: Blood
• 影响因子: 20.3
• 作者: Yijie Liu;Y. Mei;Xu Han;F. Korobova;Miguel A. Prado;Jing Yang;Zhangli Peng;J. Paulo;S. Gygi;D. Finley;P. Ji
• 通讯作者: P. Ji

mDia formins form hetero-oligomers and cooperatively maintain murine hematopoiesis.

mDia 形成异源寡聚物并协同维持小鼠造血作用。

• 发表时间: 2023-12
• 影响因子: 4.5
• 作者: Li, Zhaofeng;Su, Meng;Xie, Xinshu;Wang, Pan;Bi, Honghao;Li, Ermin;Ren, Kehan;Dong, Lili;Lv, Zhiyi;Ma, Xuezhen;Liu, Yijie;Zhao, Baobing;Peng, Yuanliang;Liu, Jing;Liu, Lu;Yang, Jing;Ji, Peng;Mei, Yang
• 通讯作者: Mei, Yang

Bone marrow-confined IL-6 signaling mediates the progression of myelodysplastic syndromes to acute myeloid leukemia.

骨髓限制的 IL-6 信号传导介导骨髓增生异常综合征向急性髓系白血病的进展。

• 发表时间: 2022-09-01
• 作者: Mei, Yang;Ren, Kehan;Liu, Yijie;Ma, Annabel;Xia, Zongjun;Han, Xu;Li, Ermin;Tariq, Hamza;Bao, Haiyan;Xie, Xinshu;Zou, Cheng;Zhang, Dingxiao;Li, Zhaofeng;Dong, Lili;Verma, Amit;Lu, Xinyan;Abaza, Yasmin;Altman, Jessica K;Sukhanova, Madina
• 通讯作者: Sukhanova, Madina