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The role of Abelson interactor 1 (Abi-1) in hematopoietic stem cell self-renewal and malignant transformation

Abelson相互作用子1（Abi-1）在造血干细胞自我更新和恶性转化中的作用

基本信息

批准号：
10651698
负责人：
Patrycja Marta Dubielecka-Szczerba
金额：
$ 36.09万
依托单位：
RHODE ISLAND HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-24 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10651698
关键词：
Actins Adaptor Signaling Protein Affect Attention Blood Bone Marrow Cell Proliferation Regulation Cells Clinical Communication Complement Critical Pathways Data Development Disease Embryo Event Genes Genetic Complementation Test Goals Heart Abnormalities Hematopoietic Hematopoietic System Hematopoietic stem cells Homeostasis Human Impairment Inflammation Inflammatory JAK2 gene Knockout Mice Knowledge Label MAP Kinase Gene Maintenance Malignant - descriptor Mediating Modeling Mus Mutation Myeloproliferative disease NF-kappa B Neoplasms Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Phosphotransferases Placenta Play Polymers Primary Myelofibrosis Process Proteins Proteomics Regulation Research Role STAT3 gene Signal Pathway Signal Transduction Technology Testing Therapeutic Transcript cancer stem cell curative treatments disease natural history fitness granulocyte hematopoietic stem cell self-renewal inhibitor insight mouse model novel novel therapeutic intervention phosphoproteomics polymerization response self-renewal src-Family Kinases stem cells therapeutic target translational goal

项目摘要

PROJECT SUMMARY/ABSTRACT It is well established that JAK/STAT signaling is dysregulated in most myeloid malignancies. Identification of JAK-activating mutations in myeloproliferative neoplasms (MPNs) prompted the development of inhibitors that target JAK for use in the clinical setting. While these agents provide a symptomatic response, they do not alter the underlying disease in that they do not target MPN-initiating malignant hematopoietic stem/progenitor cells (HSPCs). This observation has been interpreted as indicating that alternative signaling pathways contribute to the pathogenesis of MPNs. The present proposal is based on the premise that identification of hitherto unknown pathogenic mechanisms will be required to effectively treat these neoplasms and eradicate disease initiating MPN stem cells. Our long-term goal is to define signal transduction events responsible for systemic maintenance of HSPCs, with particular focus on key adapter proteins that modulate signals regulating HSPCs self-renewal, differentiation and their malignant transformation. Our direct objective is to elucidate the role of one such adapter protein, Abelson interactor-1 (Abi-1), in signaling cascades that define the HSPC phenotype. Our recent findings indicate that: (1) conditional deletion of the Abi1 gene in mouse bone marrow induces a myelofibrotic phenotype; (2) hematopoietic progenitors and granulocytes from patients with the most severe of MPNs - primary myelofibrosis (PMF) show decreased Abi-1 transcript and protein levels, and; (3) loss of Abi-1 positively affects the activity of Src Family Kinases (SFKs) and their downstream signaling to STAT3 and NF- κB, resulting in impairment of HSPC self-renewal and fitness. Our central hypothesis is that Abi-1 plays an important and potentially targetable role in HSPC self-renewal and differentiation via negative regulation of the SFK/STAT3/NF-κB inflammatory module, and that its acquired absence can promote malignant transformation and progression to PMF. Our central hypothesis will be tested in the following three Specific Aims. In Specific Aim 1 we will use our new hematopoietic cell-specific Abi-1 knockout mouse model to determine the effect of Abi-1 loss on HSPC signaling and self-renewal, differentiation and malignant transformation. In Specific Aim 2, we will use advanced proteomics combined with proximity-dependent labelling technology to define the Abi-1 interactome in HSPCs. This approach will be complemented by phosphoproteomic analyses of Abi-1-deficient HSPCs and human PMF stem/progenitor cells. In Specific Aim 3 we will use our bone marrow stroma-specific Abi-1 knockout mouse model to assess the effect of deletion of Abi-1 in the stromal component on the self-renewal, differentiation and malignant transformation of HSPCs. Completion of the proposed aims will advance our understanding of the mechanisms by which dysregulation of Abi-1/SFK/STAT3/NF-kB signaling contributes to the neoplasm-inducing capacities of HSPCs. This new knowledge will be used to make progress toward our long-term translational goal of identifying therapeutic strategies that target cells responsible for the origin of myeloproliferative neoplasms.

项目总结/文摘