Role and Mechanisms of VAV1 alterations in Peripheral T-cell Lymphomas

VAV1 改变在外周 T 细胞淋巴瘤中的作用和机制

• 批准号: 10622616
• 负责人: Teresa Palomero
• 金额: $ 36.32万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622616
• 关键词: Acceleration; Adaptor Signaling Protein; Affect; Alleles; Automobile Driving; C-terminal; CD4 Positive T Lymphocytes; Candidate Disease Gene; Cell Compartmentation; Cells; Clinical; Clonal Expansion; Cytokine Signaling; Cytoskeletal Modeling; DNA Sequence Alteration; Development; Diagnosis; Disease Progression; GATA3 gene; Genetic; Genetic Transcription; Genetically Engineered Mouse; Genomics; Goals; Guanine Nucleotide Exchange Factors; Histology; Human; Immune Evasion; Infiltration; Investigational Therapies; Knock-in Mouse; Lead; Lymphoma; Lymphomagenesis; MAP Kinase Gene; MAPK8 gene; Malignant - descriptor; Mature T-Lymphocyte; Mediating; Mus; Mutation; Mutation Analysis; Natural Killer Cells; Non-Hodgkin' s Lymphoma; Oncogenes; Oncogenic; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Pattern; Peripheral; Pharmacotherapy; Point Mutation; Pre-Clinical Model; Prognosis; Proliferating; Protein Tyrosine Kinase; Proto-Oncogenes; RHOA gene; Receptor Activation; Recurrence; Role; S100A7; Signal Pathway; Signal Transduction; Specific qualifier value; Structure of germinal center of lymph node; T cell differentiation; T-Cell Activation; T-Cell Lymphoma; T-Cell Proliferation; T-Cell Receptor; T-Cell Transformation; T-Lymphocyte; Tertiary Protein Structure; Testing; Therapeutic; Tumor Suppressor Genes; Tumor Suppressor Proteins; VAV1 gene; cell motility; cytokine; hematopoietic tissue; high risk; in vivo; individualized medicine; insertion/deletion mutation; insight; migration; molecular pathology; mouse model; novel; nuclear factors of activated T-cells; polarized cell; premalignant; programs; response; targeted sequencing; targeted treatment; therapeutic target; tool; transcriptome sequencing; tumor; tumor initiation; tumor-immune system interactions

Project Summary/Abstract Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous and poorly understood pathological group of non-Hodgkin lymphomas associated with poor prognosis. Despite major progress in recent years in the identification of genomic drivers in PTCL, understanding their mechanisms of transformation and identifying therapeutic targets remain a high priority in the field. Recently we have identified novel genetic alterations in the VAV1 oncogene in PTCL using a combination of RNAseq analysis and targeted sequencing of candidate genes. Most VAV1 genomic alterations are fusions and small intragenic deletions affecting the C-terminal domain of the protein. Our central hypothesis is that the VAV1 alterations lead to increase activation of signaling pathways downstream of VAV1 and act as oncogenic drivers of PTCL. Our preliminary results demonstrate that expression of the recurrent Vav1-myo1f fusion induces lymphomas that recapitulate the histology and molecular pathology of high-risk PTCL. The goals of this project are to characterize the mechanisms by which VAV1-MYO1F fusion promotes lymphomagenesis in vivo and to explore emerging specific therapeutic vulnerabilities in PTCL preclinical models.

项目总结/文摘