Uncovering the role for MSI2 network in hematopoietic stem cells

揭示 MSI2 网络在造血干细胞中的作用

• 批准号: 10661727
• 负责人: Michael Kharas
• 金额: $ 63.27万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661727
• 关键词: Address; Adult; Anemia; Bar Codes; Binding; Biology; Blood; Blood Cells; Bone Marrow; Cell Lineage; Cell Therapy; Cell division; Cells; Colony-Forming Units Assay; Communication; Data; Daughter; Defect; Development; Disease; Disease Progression; Dysmyelopoietic Syndromes; Engraftment; Failure; Future; Gene Expression; Genes; Genetic; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic System; Hematopoietic stem cells; Immune system; Journals; Laboratories; Lymphoid; Maintenance; Malignant Neoplasms; Mammalian Cell; Maps; Mediating; Medicine; Messenger RNA; Methods; Molecular; Morphology; Myelogenous; Nature; Normal Cell; Outcome; Pathway interactions; Patients; Phenotype; Process; Proteomics; RNA-Binding Proteins; Regulation; Role; Signal Transduction; Technology; Therapeutic; Therapeutic Intervention; Transforming Growth Factor beta; Transplantation; Work; bone marrow failure syndrome; clinical prognosis; conditional knockout; cytopenia; hematopoietic hierarchy; hematopoietic stem cell differentiation; hematopoietic stem cell fate; hematopoietic stem cell self-renewal; improved outcome; in vivo; insight; leukemia; leukemic stem cell; leukemogenesis; mouse model; new technology; novel; novel therapeutic intervention; overexpression; progenitor; programs; self-renewal; single-cell RNA sequencing; small hairpin RNA; stem; stem cell engraftment; stem cell expansion; stem cells

PROJECT SUMMARY/ABSTRACT Hematopoietic stem cells (HSCs) must navigate important cellular fate choices that include a symmetric self-renewal, symmetric commitment or undergo an asymmetric cell division where one of the cells is fated to differentiate. Alterations in this homeostatic program can lead to hematopoietic disorders and malignancies. Myelodysplastic syndromes (MDS) are a heterogeneous set of clonal disorders characterized by ineffective blood cell development. A common pathophysiologic mechanism in MDS is the presence of dysregulated hematopoietic stem and progenitor cells that fail to normally develop into the diverse set of blood cells necessary for normal function. Our laboratory and others identified MUSASHI2 (MSI2) as a central regulator of HSC and hematopoietic progenitor cell self-renewal (Kharas et al. Nature Medicine 2010). Additionally, we identified that Msi2 loss results in a defect in controlling symmetric and asymmetric division, failure to engraft and results in defective maintenance of myeloid lineage biased HSCs in part through control of the TGFβ pathway (Park et al. 2014 Journal of Experimental Medicine). We found that elevated levels of MSI2 expression predicts poor outcome and using a genetic MDS mouse model that overexpresses MSI2 can drive a more aggressive MDS (Taggart et al. 2016 Nature Communications). To determine if MSI2 is part of a regulatory network, we performed proteomics and in vivo shRNA screen for functional regulators of leukemia self-renewal. Based on this screen, we identified SYNCRIP, an RNA binding protein that shares MSI2 targets and is required in leukemia stem cells (Vu et al., 2017 Nature Genetics). Our preliminary data with a conditional knockout for Syncrip indicates that it is also critical for HSC self-renewal. Our proposal will expand our focus from MSI2 to its associated regulatory network and characterize and identify new molecular determinants for HSC and HSPC symmetric self-renewal and asymmetric fate choice. We have adapted new technologies that include a barcoding, single cell RNA-seq and paired daughter HSC assays (FATE-seq). We have also develop a new way to map direct mRNA targets in HSCs called (HYPERTRIBE), (Nguyen et al. Nature Communications 2020).This proposal will identify new regulators of HSPC fate choice which will lead to novel therapeutic strategies to improve outcomes in MDS patients.

项目总结/摘要 造血干细胞（HSC）必须导航重要的细胞命运选择，包括 对称自我更新、对称定型或经历不对称细胞分裂，其中 其中一个细胞注定要分化这种自我平衡程序的改变会导致 造血系统疾病和恶性肿瘤。骨髓增生异常综合征（MDS）是一种 以无效血细胞发育为特征的异质性克隆性疾病。一 MDS中常见的病理生理机制是存在造血功能失调， 干细胞和祖细胞不能正常发育成不同的血细胞 正常功能所必需的。我们的实验室和其他人将MUSASHI 2（MSI 2）鉴定为一种 HSC和造血祖细胞自我更新的中枢调节因子（Kharas等人，Nature Medicine 2010）。此外，我们确定Msi 2损失导致控制缺陷， 对称和不对称分裂，移植失败并导致 部分通过控制TGFβ通路，骨髓谱系偏向HSC（Park等人，2014 Journal of Experimental Medicine）。我们发现MSI 2表达水平的升高预示着 结果不佳，使用过表达MSI 2的遗传MDS小鼠模型可以驱动 更具侵袭性的MDS（Taggart et al.2016 Nature Communications）。确定MSI 2是否为 作为调控网络的一部分，我们进行了蛋白质组学和体内shRNA筛选， 白血病自我更新的调节因子。基于此筛选，我们鉴定了SYNCRIP，一种RNA， 共享MSI 2靶点并且在白血病干细胞中是必需的结合蛋白（Vu等，2017 Nature Genetics）。我们对Syncrip进行条件性敲除的初步数据表明， 也是HSC自我更新的关键。我们的建议将把我们的重点从MSI 2扩展到其 相关的调控网络，并表征和识别新的分子决定因素， HSC和HSPC对称自我更新和不对称命运选择。我们已经适应了新的 包括条形码、单细胞RNA-seq和配对子HSC测定的技术 （脂肪序列）。我们还开发了一种新的方法来定位HSC中的直接mRNA靶点，称为 （HYPERTRIBE），（Nguyen et al. Nature Communications 2020）。该提案将确定新的 HSPC命运选择的调节剂，这将带来新的治疗策略来改善 MDS患者的结局。

项目成果

MSI2 is required for maintaining activated myelodysplastic syndrome stem cells.

MSI2 是维持活化的骨髓增生异常综合征干细胞所必需的。

• DOI: 10.1038/ncomms10739
• 发表时间: 2016
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Taggart,James;Ho,Tzu-Chieh;Amin,Elianna;Xu,Haiming;Barlowe,TrevorS;Perez,AlexendarR;Durham,BenjaminH;Tivnan,Patrick;Okabe,Rachel;Chow,Arthur;Vu,Ly;Park,SunMi;Prieto,Camila;Famulare,Christopher;Patel,Minal;Lengner,Christo
• 通讯作者: Lengner,Christo

Rubbing Out Leukemia Stem Cells by Erasing the Eraser.

• DOI: 10.1016/j.stem.2020.06.009
• 发表时间: 2020-07-02
• 期刊: CELL STEM CELL
• 影响因子: 23.9
• 作者: Cheng, Yuanming;Luo, Hanzhi;Kharas, Michael G.
• 通讯作者: Kharas, Michael G.

RNA Regulators in Leukemia and Lymphoma.

• DOI: 10.1101/cshperspect.a034967
• 发表时间: 2019-10
• 期刊: Cold Spring Harbor perspectives in medicine
• 影响因子: 5.4
• 作者: Camila Prieto;M. Kharas

Design and Development of IKZF2 and CK1α Dual Degraders.

IKZF2 和 CK1α 双降解器的设计和开发。

• DOI: 10.1021/acs.jmedchem.3c01736
• 发表时间: 2023
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Miyamoto,DavidK;Curnutt,NicoleM;Park,Sun-Mi;Stavropoulos,Alexios;Kharas,MichaelG;Woo,ChristinaM
• 通讯作者: Woo,ChristinaM