IDP mediated transcriptional stabilization as a cause of AML

IDP 介导的转录稳定是 AML 的一个原因

• 批准号: 10588195
• 负责人: KATHRIN M BERNT
• 金额: $ 38.13万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588195
• 关键词: Acute Myelocytic Leukemia; Affect; Affinity; Amino Acid Sequence; Amino Acids; Androgen Receptor; Binding; Cells; Cessation of life; Chromatin; Code; Complex; Disease; Dose; EWS-FLI1 fusion protein; Enhancers; Epigenetic Process; Estrogen Receptors; Ewings sarcoma; Frequencies; Gene Expression Regulation; Genes; Genetic Transcription; Hematopoietic; Hematopoietic stem cells; Innovative Therapy; Kinetics; Leukemic Cell; Liquid substance; Malignant - descriptor; Malignant Neoplasms; Mediating; Membrane; Meningioma-1; Microscopy; Modeling; Mus; Mutation; Myelogenous; NOTCH1 gene; Nephroblastoma; Nerve Degeneration; Nuclear; Nucleosomes; Oncogenes; Oncogenic; Organelles; Outcome; Patients; Peptides; Phase Transition; Physical condensation; Physiological; Positioning Attribute; Prognosis; Property; Proteins; Regulator Genes; Reporting; Series; Site; Stretching; Structure; System; Testing; Theoretical model; Therapeutic; Variant; experimental study; inhibitor; insight; leukemia; leukemia treatment; loss of function; member; notch protein; novel strategies; novel therapeutics; overexpression; patient population; physical property; polyglutamine; preservation; progenitor; programs; promoter; recruit; stem; stem cells; targeted treatment; transcription factor; tumorigenesis

PROJECT SUMMARY High expression of the intrinsically disordered protein Meningioma-1 (MN1) is common in AML, and associated with a poor prognosis. Forced expression of MN1 in murine hematopoietic progenitors induces an aggressive leukemia. We recently discovered that the primary interaction partner of MN1 is the BAF nucleosome-positioning complex. MN1 stabilizes BAF on chromatin. MN1 binding is associated with sustained active enhancer chromatin at enhancers regulating a hematopoietic stem/progenitor program. Intriguingly, MN1’s entire coding frame is disordered. We hypothesize that MN1 causes AML by overstabilizing transcriptional hubs by increasing multi- valent, low affinity interactions that result in high local concentrations of BAF and early hematopoietic transcription factors. A better understanding of how MN1 causes leukemia may identify opportunities for targeted therapies in a patient population who is failing conventional AML therapy.

项目总结