Potential therapeutic implications of targeting miR-150 in acute myeloid leukemia

靶向 miR-150 对急性髓系白血病的潜在治疗意义

基本信息

批准号：
8984157
负责人：
Jianjun Chen
金额：
$ 33.61万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8984157
关键词：
Acute Myelocytic Leukemia Acute leukemia Address Biological Assay Bone Marrow Transplantation Chimeric Proteins Chromosomal Rearrangement Chromosomal translocation Chromosomes, Human, Pair 11 Clinic Clinical Collaborations Complement Complex Data Dendrimers Development Disease Resistance Ectopic Expression Exhibits FLT3 gene FLT3 ligand Gatekeeping Gene Delivery Gene Expression Regulation Gene Targeting Generations Genes Goals HOXA9 gene Health Hematopathology Hematopoietic Neoplasms Homeobox Human Chromosomes In Vitro Infant Lead Light MEIS1 gene MLL gene MLLT3 gene Maintenance Malignant Neoplasms Mediating MicroRNAs Mixed-Lineage Leukemia Modeling Molecular Mus Nanotechnology Oligonucleotides Oncogenes Pathogenesis Pathway interactions Patients Play Polymers Receptor Protein-Tyrosine Kinases Reporting Repression Research Research Design Role Signal Transduction Specificity System Testing Therapeutic Transcript Tumor Suppressor Proteins Untranslated RNA Viral base cancer cell cell transformation clinically significant improved in vivo interdisciplinary approach interdisciplinary collaboration interest leukemia leukemic stem cell leukemogenesis mouse model nanoparticle novel novel therapeutic intervention outcome forecast overexpression receptor response restoration self-renewal success therapy resistant treatment response

项目摘要

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is a heterogeneous group of genetically diverse hematopoietic malignancies with variable responses to treatment. Around 10% of AMLs are involved in chromosomal rearrangements of the mixed lineage leukemia (MLL) gene with over 60 fusion partners. The critical feature of MLL-rearrangements is the generation of a chimeric transcript consisting of 5' MLL and 3' sequences of a partner gene (80% involving AF9, AF6, AF10, ELL or ENL in AML). The prognosis of MLL-associated leukemia is poor. A group of important oncogenes, including homeobox A (HOXA) genes, MEIS1, FLT3, MYB, and MYC, are frequently up-regulated in MLL-associated leukemias, and play a key role in the self-renewal of leukemia stem cells (LSCs) carrying MLL-rearrangements. However, clinically significant therapies have not been developed to effectively target these genes yet. Thus, better understanding of the molecular mechanisms underlying the pathogenesis of MLL-associated leukemia, and the development of effective therapeutic strategies based on such understanding, are urgently needed. MicroRNAs (miRNA) are a class of small, non- coding RNAs that play important roles in post-transcriptional gene regulation. Very recently, we reported that miR-150 is significantly down-regulated in most AML cases, and its repression is critical for MLL-AF9-mediated cell transformation and leukemogenesis; miR-150 functions as a pivotal tumor-suppressor gatekeeper in the MLL?fusion/MYC/LIN28-miR-150?FLT3/MYB/HOXA9/MEIS1 signaling circuit, through targeting FLT3/MYB directly and MYC/LIN28/HOXA9/MEIS1 indirectly (Jiang X., et al. Cancer Cell. 2012). Hypothesis: miR-150 is required for both development and maintenance of MLL-rearranged AMLs and for the self-renewal of the relevant LSCs. Therefore, the restoration of miR-150 expression/function holds significant potential to be clinically applicable to treat this type of presently therapy-resistant disease. Specific Aims: 1) To determine whether repression of miR-150 is required for both development and maintenance of MLL-rearranged AMLs; 2) To determine whether repression of miR-150 is required for the self- renewal of LSCs of MLL-rearranged AMLs; and 3) To determine whether restoration of the expression/function of miR-150 (delivered by nanoparticles) is an effective new strategy for treating MLL-rearranged AMLs. Study Design: 1) We will use mouse bone marrow transplantation (BMT) models to determine whether ectopic expression of miR-150 can significantly inhibit both development and maintenance of all five major sub- types of MLL-rearranged AMLs (i.e., MLL-AF9, -AF6, -AF10, -ELL and -ENL). 2) We will conduct both competitive repopulation and limiting dilution assays to determine whether ectopic expression of miR-150 can significantly inhibit the self-renewal of relevant LSCs. 3) We will develop novel targeted nanoparticles based on FLT3L (FLT3 ligand)-directed dendrimers complexed with miR-150 oligos, followed by assessment of their specificity and efficacy in targeting/treating MLL-rearranged AMLs both in vitro and in vivo.

描述（由申请人提供）：急性髓细胞性白血病（AML）是一组遗传多样的造血恶性肿瘤，对治疗的反应可变。大约10％的AML参与混合谱系白血病（MLL）基因的染色体重排，具有60多个融合伴侣。 MLL重新传输的关键特征是生成伴侣基因的5'mll和3'序列的嵌合转录本（涉及AF9，AF6，AF10，AF10，ELL或AML中的80％）。与MLL相关的白血病的预后很差。一组重要的癌基因，包括同型毒素A（HOXA）基因，MEIS1，FLT3，MYB和MYC，经常在与MLL相关的白血病中上调，并且在白血病干细胞（LSC）的自我更新中起关键作用。但是，尚未开发出具有临床意义的疗法来有效地靶向这些基因。因此，迫切需要更好地理解与MLL相关性白血病发病机理的分子机制，以及基于这种理解的有效治疗策略的发展。 microRNA（miRNA）是一类小型非编码RNA，在转录后基因调节中起重要作用。最近，我们报道了MiR-150在大多数AML病例中都显着下调，并且其抑制对于MLL-AF9介导的细胞转化和白血病至关重要。 miR-150在MLL？融合/myc/lin28-mir-150？flt3/myb/hoxa9/meis1信号电路中充当一个关键的肿瘤 - 抑制者看门人，直接通过直接靶向flt3/myb和myc/lin28/lin28/hoxa9/hoxa9/meis11 indirectly（jiang x. yiang x. x. cycer）。假设：MIR-150是MLL重新启动AML的开发和维持以及相关LSC的自我更新所必需的。因此，miR-150表达/功能的恢复具有临床上可用于治疗这种类型的抗治疗的巨大潜力疾病。具体目的：1）确定MIR-150的抑制是否需要开发和维持MLL重新升级的AML； 2）确定MLL-RECRANGENED AML的LSC自我更新是否需要miR-150的抑制； 3）确定miR-150（纳米颗粒传递）的表达/功能是否恢复是治疗MLL重新传输AML的有效新策略。研究设计：1）我们将使用小鼠骨髓移植（BMT）模型来确定miR -150的异位表达是否可以显着抑制所有五种主要亚类型的MLL型AML的开发和维持（即MLL -AF9，-AF6，-AF6，-AF6，-AF10，-AF10，-AF10，-ELL和-ENL）。 2）我们将同时进行竞争性重新批量和限制稀释测定，以确定miR-150的异位表达是否可以显着抑制相关LSC的自我更新。 3）我们将基于基于FLT3L（FLT3配体）指导的树枝状大分子的新型靶向纳米颗粒，并与miR-150寡聚物复合，然后评估其在靶向/处理MLL-Rearranged Amls的特异性和功效，均在体外和体内。