The role of YTHDC1 in normal and malignant hematopoiesis

YTHDC1在正常和恶性造血中的作用

• 批准号: 10361997
• 负责人: Zhijian Qian
• 金额: $ 46.37万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-10 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10361997
• 关键词: 3-Dimensional; Acute Myelocytic Leukemia; Acute leukemia; Binding; Biological Process; Cell Proliferation; Cells; Communities; Complex; DNA Repair; DNA Sequence Rearrangement; DNA biosynthesis; Deposition; Development; Disease; Epigenetic Process; Excision; Gene Expression Regulation; Gene Mutation; Genes; Genetic; Genetic Transcription; Genomic approach; Hematology; Hematopoiesis; Hematopoietic Neoplasms; Hematopoietic stem cells; Human; In Vitro; Knowledge; Life; MLL-AF9; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Mediator of activation protein; Messenger RNA; Methylation; Methyltransferase; Modeling; Modification; Molecular; Mus; Nuclear; Nuclear Decay; Nuclear Export; Nuclear RNA; Pathogenesis; Pathway interactions; Patients; Play; Polyadenylation; Post-Transcriptional Regulation; Process; Protein Family; RNA; RNA Splicing; RNA methylation; Reader; Regulation; Reporting; Ribosomes; Role; Site; Therapeutic; Time; Up-Regulation; Xenograft procedure; acute myeloid leukemia cell; cancer type; chromatin assembly factor I; crosslinking and immunoprecipitation sequencing; effective therapy; epitranscriptome; epitranscriptomics; improved; in vivo; insight; leukemia; leukemia treatment; leukemic stem cell; leukemogenesis; mouse model; mutant; new therapeutic target; novel; overexpression; polysome profiling; self-renewal; stem; stem cell self renewal; stem cells; success; targeted treatment; transcriptome; transcriptome sequencing; transplant model; treatment strategy; tumorigenesis

ABSTRACT N6-methylation (m6A) is one of the most abundant endogenous modifications in eukaryotic mRNA. Accumulating evidence suggests that dynamic m6A RNA methylation has significant roles in multiple biological processes, and tumorigenesis by introducing another layer of post-transcriptional regulation of gene expression. Acute myeloid leukemia (AML), one of the most common types of acute leukemia, is a hematological malignant disease. In AML patients, gene mutations and genomic rearrangements often occur in hematopoietic stem/progenitor cells (HSPCs), and turn HSPCs into leukemia stem cells (LSCs), which play a central role in the development and maintenance of AML. To date, there is not an effective targeted therapy available for AML. The roles of m6A modification and its associated machinery in the pathogenesis of AML and the maintenance of LSCs/LICs remain elusive. As a nuclear m6A RNA reader that has been identified, YTHDC1 recognizes nuclear m6A-sites and acts as a critical mediator of nuclear m6A. YTHDC1 has unique roles in the regulation of nuclear RNA splicing, alternative polyadenylation, nuclear export and decay. However, its role and function in AML has not been reported yet. Our preliminary studies showed that YTHDC1 is overexpressed in human AML. We found that YTHDC1 is required for MLL-AF9-induced leukemogenesis and the survival of LSC/LIC. Thus, we hypothesize that YTHDC1 upregulation leads to post-transcriptional deregulation of a set of genes that are required for the maintenance of LSCs, thereby contributing to the pathogenesis of AML. In this proposal, we will determine 1) the role of YTHDC1 as a nuclear RNA reader in the initiation, development and maintenance of AML by regulating LSC self-renewal and survival; and 2) the underlying molecular mechanisms that mediate the role of YTHDC1 in the pathogenesis of AML. We will employ both genetic murine models as well as patient-derived xeno-transplantation (PDX) models to investigate the role of YTHDC1 in the pathogenesis of AML in vivo, and will combine transcriptome and epitranscriptome analysis to identify the key downstream targets and associated downstream pathways that mediate the role of YTHDC1 in leukemogenesis. In addition, we will elucidate molecular mechanisms by which YTHDC1 epigenetically controls the expression of its direct targets in AML cells. Our studies will define the unrecognized role of YTHDC1 in the AML development/maintenance and regulation of LSC/LIC self-renewal, quiescence and survival, and clarify the underlying mechanisms of YTHDC1. Thus, success of our project will provide new insights into the complicated mechanisms underlying epitranscriptomic regulation of leukemogenesis.

抽象的 N6-甲基化（M6A）是真核mRNA中最丰富的内源性修饰之一。 积累的证据表明，动态M6A RNA甲基化在多种生物学中具有重要作用 过程和肿瘤发生通过引入另一层的基因转录后调节 表达。急性髓样白血病（AML）是最常见的急性白血病之一，是 血液系统恶性疾病。在AML患者中，基因突变和基因组重排通常发生在 造血干/祖细胞（HSPCS），并将HSPC变成白血病干细胞（LSC），该干细胞的发挥作用 在AML的开发和维护中的核心作用。迄今为止，没有有效的目标疗法 可用于AML。 M6A修饰及其相关机器在AML和AML发病机理中的作用 LSC/LIC的维护仍然难以捉摸。作为已确定的核M6A RNA读取器 YTHDC1识别核M6A位点，并充当核M6A的关键介体。 YTHDC1具有独特性 在调节核RNA剪接，替代聚腺苷酸化，核输出和衰减中的作用。 但是，尚未报道其在AML中的作用和功能。我们的初步研究表明ythdc1 在人类AML中过表达。我们发现MLL-AF9诱导的白血病需要YTHDC1 LSC/LIC的生存。因此，我们假设ythdc1上调导致转录后 放松维护LSC所需的一组基因，从而有助于 AML的发病机理。在此提案中，我们将确定1）YTHDC1作为核RNA读取器的作用 通过调节LSC的自我更新和生存，对AML的启动，开发和维护； 2） 介导YTHDC1在AML发病机理中的作用的基本分子机制。我们将 使用遗传鼠模型以及患者衍生的异种移植（PDX）模型 研究YTHDC1在体内AML发病机理中的作用，并将结合转录组和 表参考组分析以识别下游目标和相关下游途径的关键。 介导YTHDC1在白血病中的作用。此外，我们将阐明分子机制 YTHDC1表观遗传控制其直接靶标在AML细胞中的表达。我们的研究将定义 YTHDC1在LSC/LIC自我更新的AML开发/维护和调节中的不认识的作用， 静止和存活，并阐明YTHDC1的潜在机制。因此，我们项目的成功将 提供有关对复杂机制的新见解 白血病。