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）：急性髓系白血病（AML）是一组具有不同治疗反应的遗传多样性造血系统恶性肿瘤。大约 10% 的 AML 涉及具有 60 多个融合伴侣的混合谱系白血病 (MLL) 基因的染色体重排。 MLL 重排的关键特征是生成由伴侣基因的 5' MLL 和 3' 序列组成的嵌合转录本（80% 涉及 AML 中的 AF9、AF6、AF10、ELL 或 ENL）。 MLL 相关白血病的预后很差。一组重要的癌基因，包括同源盒 A (HOXA) 基因、MEIS1、FLT3、MYB 和 MYC，在 MLL 相关白血病中频繁上调，并在白血病干细胞 (LSC) 的自我更新中发挥关键作用）携带 MLL 重排。然而，尚未开发出具有临床意义的疗法来有效靶向这些基因。因此，迫切需要更好地了解 MLL 相关白血病发病机制的分子机制，并基于这种了解制定有效的治疗策略。 MicroRNA (miRNA) 是一类小型非编码 RNA，在转录后基因调控中发挥重要作用。最近，我们报道了 miR-150 在大多数 AML 病例中显着下调，并且其抑制对于 MLL-AF9 介导的细胞转化和白血病发生至关重要； miR-150 通过直接靶向 FLT3/MYB 和间接靶向 MYC/LIN28/HOXA9/MEIS1，在 MLL?fusion/MYC/LIN28-miR-150?FLT3/MYB/HOXA9/MEIS1 信号通路中充当关键的肿瘤抑制看门人(Jiang X., et al. Cancer Cell. 2012)。假设：MLL 重排 AML 的发育和维持以及相关 LSC 的自我更新都需要 miR-150。因此，miR-150表达/功能的恢复具有在临床上适用于治疗此类目前治疗耐药的巨大潜力。疾病。具体目标： 1) 确定 MLL 重排 AML 的发生和维持是否需要抑制 miR-150； 2) 确定MLL重排的AML的LSC自我更新是否需要抑制miR-150； 3) 确定恢复 miR-150（由纳米粒子递送）的表达/功能是否是治疗 MLL 重排 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 MLL 重排 AML 的所有五种主要亚型（即 MLL-AF9）的发育和维持、-AF6、-AF10、-ELL 和 -ENL）。 2）我们将进行竞争性再增殖和有限稀释实验，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) 我们将开发基于 FLT3L（FLT3 配体）定向树枝状聚合物与 miR-150 寡核苷酸复合的新型靶向纳米颗粒，然后评估其在体外和体内靶向/治疗 MLL 重排 AML 的特异性和功效。