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

• 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
• 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

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.

项目概要/摘要 急性髓系白血病（AML），一种侵袭性白血病，其特征是异常细胞过度增殖 骨髓 (BM) 中的骨髓祖细胞，5 年存活率低于 25%。 AML 中致癌基因亲嗜性病毒整合位点 1 (EVI1) 的过度表达与较短的生存期相关 先前的研究表明，与 AML 相关的复发持续时间和较高的复发率是多因素的。 细胞周期静止的激活可以在化疗期间保护 AML 亚克隆，从而导致它们 鉴于 EVI1 过度表达 AML 的严重性，缺乏对其作用的深入了解。 EVI1在AML患者中生存期较短、复发率较高，以及目前治疗的不足 治疗策略，我们的目标是更好地了解 EVI1 相关的化疗耐药性与长期 我们的初步研究是使用 EVI1- 开发针对这种严重形式的 AML 的新疗法。 过度表达 AML 小鼠模型和患者样本表明 EVI1 过度表达激活静止 我们的 ChIP-seq 和 ATAC-seq 数据揭示了 EVI1 诱导的静止机制。 二：途径1）细胞周期蛋白依赖性激酶抑制剂1C（CDKN1C/P57kip2）的上调，这是一种关键的激活剂 造血干细胞静止，其表达与 AML 复发有关；2) 激活富含嘌呤盒结合蛋白 1 (PU.1)，这是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，我们勇敢地面对EVI1的过度表达。 通过 CDKN1C 和 PU.1 途径激活静止状态，保护 AML 细胞免受化疗的影响。 为了验证我们的假设，我们将阐明 EVI1 诱导 CDKN1C 表达的机制及其在 静止（目标 1），并研究 EVI1 中 PU.1 激活在 EVI1 相关静止（目标 2）中的作用 这将通过整合来自 RNA-seq、ChIP-seq、ATAC-seq 和的数据来完成。 其他技术来分析来自我们的体外和体内模型的 EVI1 过表达白血病细胞 将所提出的机制见解转化为临床环境和 治疗策略，我们将使用 EVI1 过表达在临床前研究中测试新的治疗方案 AML 患者来源的异种移植 (PDX) 模型（目标 3） 总之，拟议的工作将侧重于研究。 EVI1诱导的静止机制，其发现不仅有助于解释较短的存活时间 以及与 EVI1 过度表达白血病相关的较高复发率，同时也揭示了新的治疗方法 重新激活细胞周期并提高 EVI1 过表达 AML 患者生存率的策略。

项目成果

3q26.2/MECOM Rearrangements by Pericentric Inv(3): Diagnostic Challenges and Clinicopathologic Features.

Pericentric Inv(3) 的 3q26.2/MECOM 重排：诊断挑战和临床病理特征。

• 发表时间: 2023-01-11
• 影响因子: 5.2
• 作者: Tang, Zhenya;Wang, Wei;Yang, Su;El Achi, Hanadi;Fang, Hong;Nahmod, Karen Amelia;Toruner, Gokce A;Xu, Jie;Thakral, Beenu;Ayoub, Edward;Issa, Ghayas C;Yin, C Cameron;You, M James;Miranda, Roberto N;Khoury, Joseph D;Medeiros, L Jeffrey;Tang
• 通讯作者: Tang