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.

摘要 N6-甲基化(M6A)是真核基因中含量最丰富的内源性修饰之一。 越来越多的证据表明，动态m6A RNA甲基化在多种生物中具有重要作用 过程，通过引入另一层基因转录后调控而发生肿瘤 表情。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通常发生在 造血干/祖细胞(HSPC)，并将HSPC转化为白血病干细胞(LSCs)，发挥作用 在急性髓系白血病的开发和维护中发挥核心作用。到目前为止，还没有有效的靶向治疗方法。 适用于AML。M6A修饰及其相关机制在急性髓系白血病和急性髓细胞白血病发病机制中的作用 LSC/LIC的维护仍然难以捉摸。作为已经被鉴定的核m6A RNA阅读器， YTHDC1识别核M6A位点，并作为核M6A的关键调节因子。YTHDC1具有唯一性 在核RNA剪接、交替多聚腺苷、核输出和衰变的调节中的作用。 然而，其在急性髓系白血病中的作用和功能尚未见报道。我们的初步研究表明，YTHDC1 在人类急性髓系白血病中过度表达。我们发现YTHDC1在MLL-AF9诱导的白血病发生中是必需的 和LSC/LIC的生存。因此，我们假设YTHDC1上调导致转录后 解除对维持LSCs所需的一组基因的管制，从而有助于 急性髓系白血病的发病机制。在这项提案中，我们将确定1)YTHDC1作为核RNA阅读器在 通过调节LSC的自我更新和生存来启动、发展和维持AML；以及2) YTHDC1在急性髓系白血病发病机制中的作用。我们会 利用遗传小鼠模型和患者来源的异种移植(PDX)模型 研究YTHDC1在AML体内发病机制中的作用，并将转录组和 表位转录组分析，以确定关键的下游目标和相关的下游途径 介导YTHDC1在白血病发生中的作用。此外，我们还将阐明其分子机制 YTHDC1在表观遗传学上控制其在AML细胞中的直接靶标的表达。我们的研究将定义 YTHDC1在急性髓系白血病的发展/维持和调节LSC/LIC自我更新中的未被认识的作用， 静息和存活，并阐明YTHDC1的潜在机制。因此，我们项目的成功将 为表位转录调控的复杂机制提供了新的见解 白血病的发生。