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（m6 A）是真核生物mRNA中最丰富的内源性修饰之一。 越来越多的证据表明，动态m6 A RNA甲基化在多种生物学行为中具有重要作用， 过程，并通过引入另一层基因转录后调控的肿瘤发生 表情急性髓性白血病（AML）是最常见的急性白血病类型之一，是一种急性白血病。 恶性血液病在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HSPCs转化为白血病干细胞（LSC），后者在造血干/祖细胞（HSPCs）中发挥重要作用。 在AML的发展和维持中发挥核心作用。迄今为止，还没有有效的靶向治疗 可用于AML。m6 A修饰及其相关机制在AML发病机制中的作用， LSC/LIC的维持仍然难以捉摸。作为已经鉴定的核m6 A RNA阅读器， YTHDC 1识别核m6 A位点，并作为核m6 A的关键介质。YTHDC 1具有独特的 在调节核RNA剪接、选择性多聚腺苷酸化、核输出和衰变中的作用。 然而，其在AML中的作用和功能尚未报道。我们的初步研究表明，YTHDC 1 在人类AML中过度表达。我们发现YTHDC 1是MLL-AF 9诱导的白血病发生所必需的 和LSC/LIC的生存。因此，我们假设YTHDC 1上调导致转录后的 维持LSC所需的一组基因的失调，从而有助于 AML的发病机制。在这个提议中，我们将确定1）YTHDC 1作为核RNA阅读器在以下方面的作用： 通过调节LSC的自我更新和存活来启动、发展和维持AML;和2） 介导YTHDC 1在AML发病机制中作用的潜在分子机制。我们将 采用遗传小鼠模型以及患者来源的异种移植（PDX）模型， 研究YTHDC 1在体内AML发病机制中的作用，并将联合收割机转录组和 表位转录组分析，以确定关键的下游靶点和相关的下游途径， 介导YTHDC 1在白血病发生中的作用。此外，我们将阐明分子机制， YTHDC 1在表观遗传学上控制其直接靶点在AML细胞中的表达。我们的研究将定义 YTHDC 1在AML发展/维持和LSC/LIC自我更新调节中的未被认识的作用， 静止和存活，并阐明YTHDC 1的潜在机制。因此，我们项目的成功将 提供了新的见解，复杂的机制，潜在的epitranscriptomic调节 白血病发生