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Elucidating the Functional and Mechanistic Roles of LINE-1 Retrotransposons in Myeloid Leukemia

阐明 LINE-1 逆转录转座子在髓系白血病中的功能和机制作用

基本信息

批准号：
10860830
负责人：
Jian Xu
金额：
$ 47.98万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10860830
关键词：
Acute Myelocytic Leukemia Affect Biology CRISPR interference CRISPR screen CRISPR-mediated transcriptional activation Cell Cycle Cells Chemoresistance Chromatin Chromosome abnormality Clonal Evolution Complex DNA DNA Damage DNA Sequence Alteration DNA Transposable Elements Dependence Development Disease Elements Epigenetic Process Functional disorder Generations Genetic Genomic Instability Genomics Goals Hematopoiesis Hematopoietic stem cells Human Human Genome Impairment In Vitro Inflammatory Insertional Mutagenesis Interferon Type I Intervention Junk DNA L1 Elements Length Link Long Interspersed Elements Maintenance Malignant - descriptor Malignant Neoplasms Mediating Messenger RNA Modeling Molecular Mus Myelogenous Myeloid Leukemia Oncogenes Pathogenesis Pathway interactions Patients Phenocopy Phenotype Physiological Prognosis Prognostic Marker Proteins Regulatory Pathway Repression Resistance Retrotransposition Retrotransposon Role Signal Pathway Signal Transduction Somatic Mutation Source Testing Therapeutic Transgenic Organisms Untranslated RNA Variant Work Xenograft procedure acute myeloid leukemia cell antileukemic agent cancer initiation epigenetic regulation epigenetic silencing genome integrity high risk human DNA improved in vivo innovation leukemia leukemia initiating cell leukemia treatment leukemogenesis mouse model overexpression pharmacologic response self-renewal targeted treatment transposon/insertion element treatment response tumor

项目摘要

PROJECT SUMMARY The role of retrotransposons in human cancer has been historically underappreciated both because they have been dismissed as unimportant ‘junk’ DNA, and because their high repetition and variation pose significant technical challenges. There are ~500,000 copies of LINE-1 (or L1) retrotransposons occupying 17% of the human genome, but only ~100 full-length human-specific L1 elements (L1Hs) are capable of active retrotransposition. L1-encoded proteins also mobilize non-autonomous retrotransposons, noncoding RNAs and mRNAs, leading to the generation of a third of human DNA. As such, L1s have been considered mostly deleterious because their activity can lead to genetic mutations and chromosomal alterations that contribute to human disorders including cancer. By domain-based CRISPR screens of human chromatin regulators, we identified MPP8, a component of the HUSH complex responsible for the silencing of L1 retrotransposons, as a selective epigenetic dependency of acute myeloid leukemia (AML) cells. While dispensable for normal hematopoiesis, MPP8 loss impaired AML initiation and maintenance by reactivating L1s. Ectopic L1 activation phenocopied MPP8 loss, whereas blocking L1 retrotransposition abrogated the phenotypes. L1 suppression is associated with therapy resistance and poor prognosis in human AML patients. Hence, while retrotransposons are historically recognized for their cancer-promoting roles as sources of genetic instability and somatic mutations, our findings support an unexpected ‘tumor-suppressive’ function for retrotransposons as a selective dependency for myeloid leukemia. The goal of this project is to elucidate the functional and mechanistic roles of L1 retrotransposons as a new regulatory pathway in AML pathophysiology. The central hypotheses are that L1 retrotransposons function to modulate DNA damage response and/or inflammatory signaling in AML-initiating cells, and that L1 activity controls therapeutic response to DNA damage-inducing agents in myeloid leukemia. Our hypotheses have been formulated on the basis of extensive preliminary studies using orthogonal approaches to modulate L1 function in physiologically relevant AML models and a newly discovered molecular link between suppression of retrotransposons and propagation of cancer-initiating cells. Guided by these findings, these hypotheses will be tested by three specific aims: 1) Establish the functional roles of L1 retrotransposons in the clonal evolution of myeloid leukemia. 2) Elucidate the mechanistic roles of L1 retrotransposons in AML pathogenesis. 3) Determine the effects of modulating retrotransposon activity on therapeutic response to DNA damage-inducing agents in myeloid leukemia. Taken together, these studies will not only elucidate the mechanistic basis for the unexpected ‘tumor-suppressive’ function for retrotransposon activity in myeloid leukemia, but also establish a new paradigm for mobile DNA elements as a previously uncharted regulatory pathway in leukemia biology, whose intervention may lead to improved anti-leukemia therapies.

项目总结