Experimental and preclinical modeling of NUP98-rearranged acute leukemia

NUP98重排急性白血病的实验和临床前模型

• 批准号: 10228888
• 负责人: RICHARD W KRIWACKI
• 金额: $ 2.28万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228888
• 关键词: ATAC-seq; Acute Erythroblastic Leukemia; Acute Myelocytic Leukemia; Acute leukemia; Address; Biochemical; Biological Assay; C-terminal; Cell Nucleus; Cells; ChIP-seq; Childhood Acute Myeloid Leukemia; Chromatin; Chromatin Structure; Coupled; Coupling; Disease; Distal; Epigenetic Process; Exhibits; Experimental Models; Fluorescence; Fluorescence Microscopy; Fluorescence Recovery After Photobleaching; Fusion Oncogene Proteins; Gel; Gene Expression; Genes; Genetic Transcription; HOXA9 gene; Hematologic Neoplasms; Hematopoietic; In Vitro; Knowledge; Length; Liquid substance; Mediating; Methods; Molecular; Mutagenesis; N-terminal; NUP98 gene; Neutrons; Nuclear; Nuclear Magnetic Resonance; Nuclear Pore Complex Proteins; Oncogenes; Other Genetics; Phase; Pre-Clinical Model; Property; Proteins; RNA; Regulator Genes; Resolution; Roentgen Rays; Site; Structure; Testing; Treatment outcome; biophysical techniques; cell transformation; crosslink; genetic regulatory protein; genome editing; genomic locus; insight; leukemia; leukemogenesis; metaplastic cell transformation; microscopic imaging; outcome forecast; recruit; single molecule; submicron; therapeutic development; transcriptome sequencing; viscoelasticity

Project 3/Summary NUP98 fusion oncogenes (e.g., NUP98-HOXA9, -KDM5A, and -NSD1) are associated with several hematological malignancies, including pediatric acute myeloid leukemia (AML), characterized by dismal treatment outcomes. The N-terminal FG-repeat domain that is common to all NUP98 fusion oncogenes (termed NUP98-N) is known to be intrinsically disordered and, by itself, to undergo phase separation to form gel-like bodies in vitro and large, spherical puncta in the nuclei of cells. However, these large puncta are not associated with hematopoietic cell transformation and leukemogenesis. Importantly, NUP98 fusion oncoproteins (FOs)—in which NUP98-N is fused to a variety of different C-terminal chromatin targeting domains—form many chromatin-associated, sub-micron-sized puncta that are associated with aberrant gene transcription, hematopoietic cell transformation and leukemogenesis. Recently, Young, et al., Tjian, et al., and Rivera, et al., demonstrated that critical transcriptional regulators, i) exhibit disordered regions that undergo phase separation in vitro and ii) are found within small, liquid-like puncta in cells that are proposed to form through phase separation. These dynamic puncta are proposed to drive co-localization of distal chromatin sites and organize the transcriptional machinery for coordinated expression of multiple genes. In the proposed studies, we will test the hypothesis that phase separation is a unifying mechanism that drives the formation of aberrant transcription centers by NUP98 FOs at chromatin sites targeted by their various C-terminal fused domains. These aberrant transcription centers, we propose, recruit components of the transcriptional machinery to activate expression of HOX and other genes and transform hematopoietic cells. 1

项目3/总结 NUP98融合癌基因(例如，NUP98-HOXA9、-KDM5A和-NSD1)与几个 血液系统恶性肿瘤，包括儿童急性髓系白血病(AML)，其特征是 治疗结果。所有NUP98融合癌基因共有的N-末端FG-重复结构域 (称为NUP98-N)已知本质上是无序的，并且本身经历相分离以形成 体外可见凝胶状小体，细胞核内可见大而圆的点状颗粒。然而，这些大标点并不是 与造血细胞转化和白血病发生有关。重要的是，NUP98融合 癌蛋白(FOS)-其中NUP98-N与多种不同的C末端染色质靶向融合 结构域-形成许多染色质相关的亚微米大小的斑点，与异常基因有关 转录、造血细胞转化和白血病发生。最近，Young等人、Tian等人和 Rivera等人证明了关键的转录调节因子，i)表现出经历 体外相分离和ii)在拟形成的细胞中发现小的液状点状。 通过相分离。这些动态的斑点被提出来驱动远端染色质位点的共同定位 并组织转录机制以协调多个基因的表达。在建议的 研究中，我们将检验这样的假设，即相分离是驱动形成 不同C末端融合靶向染色质部位的NUP98 FOS异常转录中心 域名。我们认为，这些异常的转录中心招募了转录的成分 激活HOX和其他基因的表达并转化造血细胞的机制。 1