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Dissecting the functional role of LINE1 retrotransposon-mediated interferon signaling in myeloid leukemia

剖析 LINE1 逆转录转座子介导的干扰素信号在髓系白血病中的功能作用

基本信息

批准号：
10536349
负责人：
Michael Lee
金额：
$ 3.77万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-18 至 2026-07-17
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10536349
关键词：
Ablation Acute Myelocytic Leukemia Address Adult Affect Apoptosis Biology CRISPR-mediated transcriptional activation Cell Aging Cell Cycle Arrest Cell Proliferation Clustered Regularly Interspaced Short Palindromic Repeats Complementary DNA DNA Dependence Development Double-Stranded RNA Elements Epigenetic Process Gene Expression Regulation Genetic Genetic Transcription Genetic study Genome Stability Genomic DNA Hematologic Neoplasms Hematopoiesis Hematopoietic Hematopoietic Neoplasms Human Immune Impairment In Vitro Individual Inflammation Innate Immune Response Interferon Activation Interferon Type I Interferons Jumping Genes Knockout Mice Knowledge Link Long Interspersed Elements MLL-AF9 Maintenance Malignant - descriptor Malignant Neoplasms Mediating Modeling Molecular Mus Myelogenous Myeloid Leukemia Natural Immunity Nature Nucleic Acids Pathogenesis Pathway interactions Patients RNA Reporting Repression Retrotransposition Retrotransposon Reverse Transcription Role Signal Pathway Signal Transduction Survival Rate Therapeutic Transcript Transgenic Mice Viral Work Xenograft procedure acute myeloid leukemia cell base cancer type chemotherapy clinical heterogeneity epigenetic silencing gene product in vivo inhibitor knock-down leukemia leukemia initiating cell leukemogenesis mimicry mouse model mutant novel therapeutics overexpression receptor response self-renewal sensor small hairpin RNA standard of care targeted treatment tumor tumorigenesis

项目摘要

PROJECT SUMMARY Acute myeloid leukemia (AML) is one of the most aggressive hematologic malignancies in adults, yet decades- old chemotherapies remain the standard of care and few targeted therapies exist owing to its molecular and clinical heterogeneity. An emerging hallmark of AML development is the epigenetic silencing of LINE1 retrotransposons which is required to maintain AML self-renewal, differentiation blockade, and genomic stability. Aberrant reactivation of LINE1 retrotransposons selectively impairs propagation of human and mouse AML cells without affecting normal hematopoiesis; however, it remains elusive how LINE1 activity inhibits myeloid leukemogenesis. Aberrant retrotransposon reactivation by cancer-targeting epigenetic inhibitors such as DNA hypomethylating agents (DMA) produces a type I interferon (IFN)-mediated ‘viral mimicry’ response in various cancer types, including leukemias, resulting in cell cycle arrest and apoptosis. We hypothesize that LINE1 retrotransposons contribute to the development of myeloid leukemia by modulating type I interferon signaling mediated by cGAS and/or RIG-I-like Receptor (RLR) sensing of LINE1 gene products. This proposal will establish the functional role of LINE1-mediated IFN signaling in myeloid leukemogenesis and determine the mechanisms by which LINE1 activates innate immune ‘viral mimicry’ pathways in AML cells. The Specific Aims of this proposal intend to 1) establish the functional role of LINE1-mediated interferon signaling in myeloid leukemogenesis and progression; and 2) identify the molecular sensors of LINE1-mediated interferon activation in AML. Ectopic LINE1 overexpression and CRISPR activation of endogenous LINE1s in human AML cells will determine whether LINE1 expression induces type I IFNs and impacts cell proliferation, myeloid differentiation, and/or apoptosis. Combining a conditional LINE1 activation transgenic mouse with the established MLL-AF9 retroviral leukemia model will determine whether activation of LINE1s induces hematopoietic-specific type I IFN to impair AML initiation and/or maintenance in vivo. Moreover, genetic ablation of cGAS, RIG-I, or MDA5 nucleic acid sensors individually or in combination in human AML cells and their corresponding knockout mouse models will determine how loss of DNA- and/or RNA-sensing pathways affects LINE1-induced inflammation and AML pathogenesis in vivo. Altogether, these stringent genetic studies will provide direct evidence to establish the functional role of LINE1-mediated IFN signaling in myeloid leukemia. Addressing these outstanding knowledge gaps will be critical to inform whether and how modulation of the retrotransposon-innate immunity crosstalk may be leveraged as a new mechanism-based therapeutic strategy to selectively eradicate AML cells.

项目摘要急性髓性白血病（AML）是成人中最具侵袭性的血液恶性肿瘤之一，然而几十年来，旧的化学疗法仍然是护理的标准，并且由于其分子和生物学特性，临床异质性AML发展的一个新的标志是LINE 1的表观遗传沉默逆转录转座子是维持AML自我更新、分化阻断和基因组稳定性所需的。 LINE 1反转录转座子的异常再激活选择性地损害人和小鼠AML细胞的增殖而不影响正常的造血;然而，LINE 1活性如何抑制髓系造血仍然是难以捉摸的。白血病发生通过癌症靶向表观遗传抑制剂如DNA的异常反转录转座子再激活低甲基化剂（DMA）在多种细胞中产生I型干扰素（IFN）介导的“病毒模拟”应答。癌症类型，包括白血病，导致细胞周期停滞和细胞凋亡。我们假设LINE 1 逆转录转座子通过调节I型干扰素信号通路促进髓性白血病的发展由LINE 1基因产物的cGAS和/或RIG-I样受体（RLR）传感介导。这项建议会确立LINE 1介导的IFN信号在髓系白血病发生中的功能作用，并确定 LINE 1激活AML细胞中先天免疫“病毒模拟”途径的机制。具体目标本提案的目的是：1）确定LINE 1介导的干扰素信号传导在骨髓中的功能作用，白血病的发生和发展; 2）确定LINE 1介导的干扰素激活的分子传感器在AML。人AML细胞中的异位LINE 1过表达和内源性LINE 1的CRISPR活化将导致人AML细胞中的内源性LINE 1的表达增加。确定LINE 1表达是否诱导I型IFN并影响细胞增殖，骨髓分化，和/或凋亡。将条件性LINE 1活化转基因小鼠与建立的MLL-AF 9组合逆转录病毒白血病模型将确定LINE 1 s的激活是否诱导造血特异性I型IFN 损害体内AML的启动和/或维持。此外，cGAS、RIG-I或MDA 5核酸的基因消融可用于治疗癌症。在人AML细胞及其相应的敲除小鼠模型中单独或组合的酸传感器将确定DNA和/或RNA传感通路的丢失如何影响LINE 1诱导的炎症和AML 体内发病机制。总之，这些严格的遗传学研究将提供直接证据，以建立 LINE 1介导的IFN信号在髓系白血病中的功能作用解决这些突出的知识缺口将是至关重要的，以告知是否以及如何调节逆转录转座子先天免疫串扰，作为一种新的基于机制的治疗策略，选择性地根除AML细胞。