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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：
10670097
负责人：
Michael Lee
金额：
$ 4.15万
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/10670097
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 cancer type chemotherapy clinical heterogeneity cross immunity epigenetic silencing feature detection 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.

项目总结