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 中最丰富的内源修饰之一。 越来越多的证据表明动态 m6A RNA 甲基化在多种生物学中具有重要作用 通过引入另一层基因转录后调控来控制过程和肿瘤发生 表达。急性髓系白血病 (AML) 是最常见的急性白血病类型之一，是一种 血液系统恶性疾病。在 AML 患者中，基因突变和基因组重排经常发生在 造血干/祖细胞（HSPC），并将 HSPC 转化为白血病干细胞（LSC），发挥 在 AML 的发展和维护中发挥核心作用。迄今为止，尚无有效的靶向治疗方法 可用于反洗钱。 m6A 修饰及其相关机制在 AML 和 AML 发病机制中的作用 LSC/LIC 的维护仍然难以实现。作为已鉴定的核 m6A RNA 阅读器， YTHDC1 识别核 m6A 位点并充当核 m6A 的关键介质。 YTHDC1具有独特的 在核 RNA 剪接、选择性聚腺苷酸化、核输出和衰变的调节中发挥作用。 但其在AML中的作用和功能尚未见报道。我们的初步研究表明YTHDC1 在人类 AML 中过度表达。我们发现 YTHDC1 是 MLL-AF9 诱导的白血病发生所必需的 以及 LSC/LIC 的生存。因此，我们假设 YTHDC1 上调导致转录后 解除对维持 LSC 所需的一组基因的管制，从而有助于 AML 的发病机制。在本提案中，我们将确定 1) YTHDC1 作为核 RNA 阅读器的作用 通过调节LSC自我更新和生存来引发、发展和维持AML；和 2） 介导 YTHDC1 在 AML 发病机制中作用的潜在分子机制。我们将 采用遗传鼠模型以及患者来源的异种移植（PDX）模型 研究YTHDC1在体内AML发病机制中的作用，并将结合转录组和 表观转录组分析以确定关键的下游靶点和相关的下游途径 介导 YTHDC1 在白血病发生中的作用。此外，我们将阐明其分子机制 YTHDC1 通过表观遗传学控制其直接靶标在 AML 细胞中的表达。我们的研究将定义 YTHDC1 在 AML 发展/维持和 LSC/LIC 自我更新调节中的作用尚未被认识到， 静止和存活，并阐明 YTHDC1 的潜在机制。因此，我们的项目的成功将 为表观转录组调控的复杂机制提供新的见解 白血病发生。