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.

项目摘要/摘要急性髓细胞性白血病（AML），一种侵略性白血病，其特征是异常的增殖骨髓（BM）中的髓样祖细胞，携带5年的存活率小于25％。 AML中癌基因生态病毒整合位点1（EVI1）的过表达与较短的生存有关持续时间和更高的继电器率。 AML相关的继电器是多因素的，先前的研究表明细胞周期静止的激活在化学疗法过程中保护AML亚克隆，导致其生存。鉴于EVI1过表达AML的严重性，缺乏对角色的深入了解 AML患者较短的生存期和更高的继电器率的EVI1，并且当前的不足治疗策略，我们旨在更好地了解EVI1相关的化学耐药性为这种几种形式的AML开发新疗法的术语目标。我们使用EVI1-的初步研究过表达的AML小鼠模型和患者样品表明EVI1过表达激活静止途径。我们的chip-seq和atac-seq数据表明，EVI1诱导的静止的机理涉及两种途径：1）细胞周期蛋白依赖性激酶抑制剂1C（CDKN1C/P57KIP2）的上调，一种临界激活剂造血干细胞静止，其表达与AML继电器有关； 2）激活购买盒结合蛋白1（PU.1）的激活，骨髓虫的主要调节剂，足以触发造血干细胞（HSC）中的细胞周期静止。那我们假设EVI1过表达通过通过CDKN1C和PU.1途径激活静止，保护AML细胞免受化学疗法。为了检验我们的假设，我们将阐明EVI1诱导的CDKN1C表达的机理及其在静止（AIM 1），并研究PU.1激活在EVI1-与EVI1-相关的静止（AIM 2）中的作用过表达AML。这将通过整合RNA-Seq，Chip-Seq，Atac-Seq和从我们的体外和体内模型中分析过表达EVI1的白血病细胞的其他技术以及原代人AML样品。将拟议的机械见解转化为临床环境和治疗策略，我们将使用EVI1过表达的临床前研究测试新的治疗方案 AML患者衍生的异种移植（PDX）模型（AIM 3）。总而言之，拟议的工作将集中于调查 EVI1诱导的静止机制及其发现不仅有助于解释较短的生存时间以及与过表达EVI1的白血病相关的较高的继电器率，但也推出了新疗法重新激活细胞周期并改善EVI1过表达AML患者存活的策略。