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Targeting Quiescence Pathways to Overcome Chemoresistance in EVI1-Overexpressing Leukemia

靶向静止途径克服 EVI1 过表达白血病的化疗耐药性

基本信息

批准号：
10630823
负责人：
Edward Ayoub
金额：
$ 7.45万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
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：
2022-04-05 至 2025-04-04
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630823
关键词：
3q26 ATAC-seq Acute Myelocytic Leukemia Address Adult Acute Myeloblastic Leukemia Aftercare Binding Binding Proteins Binding Sites Bone Marrow CDKN1C gene Cell Cycle Cell Line Cell model ChIP-seq Chemoresistance Chromatin Chromosomes Clinical Clinical Data Clinical Treatment Clinical Trials Collaborations Complex Cyclin-Dependent Kinase Inhibitor DNA Binding Data Disease-Free Survival EVI1 gene EZH2 gene Enhancers Future Genes Genetic Transcription Goals Granulocyte Colony-Stimulating Factor Health Hematopoiesis Hematopoietic stem cells Human In Vitro Inflammatory Laboratories Leukemic Cell Link Molecular Molecular Analysis Mus Myelogenous Myeloid Progenitor Cells Myelopoiesis Myeloproliferative disease Neoadjuvant Therapy Oncogenes Pathway interactions Patients Play Progression-Free Survivals Proliferating Purines RUNX1 gene Regulation Relapse Research Research Personnel Role Sampling Severities Stress Survival Rate Techniques Testing Therapeutic Training Transcription Initiation Site Translating Treatment Protocols Up-Regulation Upstream Enhancer Work Xenograft Model acute myeloid leukemia cell chemotherapy chromatin immunoprecipitation clinically relevant data integration genomic data hematopoietic stem cell quiescence improved in vivo Model individualized medicine inhibitor insight knock-down lambda Spi-1 leukemia leukemia relapse mouse model novel novel therapeutic intervention novel therapeutics overexpression patient derived xenograft model preclinical study response small hairpin RNA transcription factor transcriptome sequencing treatment response

项目摘要

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML), an aggressive leukemia characterized by the excessive proliferation of abnormal myeloid progenitor cells in the bone marrow (BM), and carries a 5-year survival rate less than 25%. Overexpression of the oncogene ecotropic viral integration site 1 (EVI1) in AML is associated with shorter survival durations and higher relapse rates. AML-associated relapse is multifactorial, and previous studies have shown that the activation of cell cycle quiescence protects AML subclones during chemotherapy, resulting in their survival. Given the severity of EVI1-overexpressing AML, the lack of an in-depth understanding of the role of EVI1 in AML patients’ shorter survival durations and higher relapse rates, and the inadequacy of current therapeutic strategies, we aim to gain a better understanding of EVI1-associated chemoresistance with the long- term goal of developing novel therapies for this sever form of AML. Our preliminary studies using an EVI1- overexpressing AML mouse model and patient samples indicate that EVI1 overexpression activates quiescence pathways. Our ChIP-seq and ATAC-seq data revealed that the mechanism of EVI1-induced quiescence involves two pathways: 1) the upregulation of cyclin-dependent kinase inhibitor 1C (CDKN1C/P57kip2), a critical activator of hematopoietic stem cell quiescence, whose expression has been linked with AML relapse; and 2) the activation of purine-rich box binding protein 1 (PU.1), a master regulator of myelopoiesis, which is sufficient to trigger cell cycle quiescence in hematopoietic stem cells (HSCs). Thus, we hypothesize that EVI1 overexpression protects AML cells from chemotherapy by activating quiescence through CDKN1C and PU.1 pathways. To test our hypothesis, we will elucidate the mechanism of EVI1-induced CDKN1C expression and its role in quiescence (Aim 1), and investigate the role of PU.1 activation in EVI1-associated quiescence (Aim 2) in EVI1- overexpressing AML. This will be accomplished by integrating data from RNA-seq, ChIP-seq, ATAC-seq, and other techniques to analyze EVI1-overexpressing leukemia cells from our in vitro and in vivo models and from primary human AML samples. To translate the proposed mechanistic insights into clinical settings and therapeutic strategies, we will test new treatment regiments in preclinical studies using EVI1-overexpressing AML patient-derived xenograft (PDX) models (Aim 3). In summary, the proposed work will focus on investigating EVI1-induced quiescence mechanisms, and its findings will not only help explain the shorter survival durations and higher relapse rates associated with EVI1-overexpressing leukemia but also unveil new therapeutic strategies that reactivate the cell cycle and improve the survival of patients with EVI1-overexpressing AML.

项目总结/摘要急性髓系白血病（AML）是一种侵袭性白血病，其特征在于异常的骨髓细胞过度增殖，骨髓（BM）中的髓系祖细胞，5年存活率低于25%。癌基因亲嗜性病毒整合位点1（EVI 1）在AML中的过表达与较短的生存期相关持续时间和更高的复发率。AML相关复发是多因素的，先前的研究表明，细胞周期静止期的激活在化疗期间保护AML亚克隆，导致其生存考虑到EVI 1过表达AML的严重性，缺乏对EVI 1在AML中的作用的深入了解， AML患者中EVI 1的生存期较短，复发率较高，而目前对EVI 1的研究不足，治疗策略，我们的目标是更好地了解EVI 1相关的化疗耐药性与长期的，长期目标是为这种严重形式的AML开发新的疗法。我们的初步研究使用EVI 1- 过表达AML小鼠模型和患者样品表明，EVI 1过表达激活了静止路径。我们的ChIP-seq和ATAC-seq数据显示，EVI 1诱导的静止机制涉及两条途径：1）细胞周期蛋白依赖性激酶抑制剂1C（CDKN 1C/P57 kip 2）的上调，造血干细胞静止，其表达与AML复发有关;和2）激活富含嘌呤的盒结合蛋白1（PU.1），一种骨髓生成的主要调节因子，足以触发造血干细胞（HSC）的细胞周期静止。因此，我们假设EVI 1过表达通过CDKN 1C和PU.1通路激活静止期，保护AML细胞免受化疗。为了验证我们的假设，我们将阐明EVI 1诱导的CDKN 1C表达的机制及其在细胞凋亡中的作用。静止（目的1），并研究PU.1激活在EVI 1相关静止（目的2）中的作用。过度表达AML。这将通过整合来自RNA-seq、ChIP-seq、ATAC-seq和其他技术来分析来自我们的体外和体内模型的EVI 1过表达白血病细胞，原代人AML样品。将提出的机制见解转化为临床环境，治疗策略，我们将在临床前研究中使用EVI 1-过表达 AML患者来源的异种移植物（PDX）模型（Aim 3）。综上所述，本次拟开展的工作重点是调查 EVI 1诱导的静止机制，其研究结果不仅有助于解释较短的生存期，和更高的复发率与EVI 1过度表达白血病相关，但也揭示了新的治疗方法重新激活细胞周期和改善EVI 1过表达AML患者生存的策略。