Functional Genomic Dissection of Refractory Anemia

难治性贫血的功能基因组解析

• 批准号: 10190995
• 负责人: Benjamin Levine Ebert
• 金额: $ 44.13万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190995
• 关键词: Acute leukemia; Address; Affinity; Amino Acids; Apoptosis; Binding; Biochemistry; Biological; Biology; Blood; Bone Marrow; Bypass; CRISPR screen; CSNK1A1 gene; Cell Cycle Progression; Cells; Chromosome Deletion; Chromosome abnormality; Cytogenetics; Development; Disease; Dissection; Drug resistance; Dysmyelopoietic Syndromes; Funding; Genes; Genetic; Hematopoietic; Homeostasis; Human; Immune system; Knock-in Mouse; Knockout Mice; Lesion; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Modeling; Molecular; Mus; Mutation; Oncoproteins; Patients; Pharmaceutical Preparations; Production; Proteins; Refractory anemias; Resistance; Role; Series; Set protein; TP53 gene; Thalidomide; Therapeutic; Toxic effect; Translations; Transplantation; Treatment Efficacy; Ubiquitination; Wild Type Mouse; base; casein kinase I; chromosome 5q loss; combinatorial; conditional knockout; cytotoxicity; drug efficacy; effective therapy; efficacy evaluation; experimental study; functional genomics; genome-wide; in vivo; lenalidomide; mouse model; mutant; novel; novel therapeutic intervention; novel therapeutics; resistance mechanism; response; stem cells; therapeutic target; treatment strategy; ubiquitin ligase; ubiquitin-protein ligase

ABSTRACT Lenalidomide is a highly effective treatment for patients with myelodysplastic syndrome (MDS) with deletion of Chromosome 5q (del(5q)), with approximately 50% of patients achieving a complete cytogenetic response. In the previous funding period, we determined the mechanistic basis for the therapeutic efficacy of lenalidomide in del(5q) MDS, generated the first murine model that responds to lenalidomide, and developed a quantitative mass spectrometry-based approach to evaluate the activity of lenalidomide and related molecules. We now propose to investigate the molecular basis for incomplete responses to lenalidomide and acquired resistance, and to develop a novel therapeutic approach that bypasses resistance. First, we aim to determine mechanisms of sensitivity and resistance that have not been previously investigated: the impact of lenalidomide on stem cells, the bone marrow microenvironment, and the immune system. These experiments are enabled by the CRBNI391V murine model, developed during the previous funding period, that is sensitive to lenalidomide. Next, we will examine combinatorial targeting of CSNK1A1 and GSPT1 with a new thalidomide derivative, CC-885, and investigate the mechanism of GSPT1-mediated cytotoxicity in models of del(5q) MDS. Finally, we will investigate the biochemistry of lenalidomide-dependent degradation of oncoproteins by the CRL4CRBN E3 ubiquitin ligase, validating genes identified through genome-wide CRISPR screens. These studies will inform the biology of thalidomide derivatives in general, provide a comprehensive description and mechanistic understanding of thalidomide derivative effects on immune system homeostasis, and contribute to the development of novel therapeutics for del(5q) MDS.

摘要