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

• 批准号: 8615676
• 负责人: Jianjun Chen
• 金额: $ 34.32万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 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/8615676
• 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 Trials; Collaborations; Complement; Complex; DNA Sequence Rearrangement; Data; Dendrimers; Development; Disease Resistance; Ectopic Expression; Exhibits; FLT3 gene; FLT3 ligand; Functional RNA; Gatekeeping; Gene Delivery; Gene Expression Regulation; Gene Targeting; Generations; Genes; Goals; HOXA9 gene; Health; Hematologic Neoplasms; Hematopathology; Hematopoietic Neoplasms; Homeobox; Human Chromosomes; In Vitro; Infant; Lead; Light; MEIS1 gene; MLL gene; MLLT3 gene; MLLT4 gene; Maintenance; Malignant Neoplasms; Mediating; MicroRNAs; Modeling; Molecular; Mus; Nanotechnology; Oncogenes; Pathogenesis; Pathway interactions; Patients; Play; Polymers; Receptor Protein-Tyrosine Kinases; Reporting; Repression; Research; Research Design; Role; Signal Transduction; Specificity; System; Testing; Therapeutic; Toxic effect; Transcript; Tumor Suppressor Proteins; 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

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(申请人提供)：急性髓系白血病(AML)是一组遗传多样性的血液系统恶性肿瘤，对治疗的反应各不相同。大约10%的AML参与了混合系白血病(MLL)基因的染色体重排，有60多个融合伙伴。MLL重排的关键特征是产生由5‘MLL和3’序列组成的嵌合转录本(AML中80%涉及AF9、AF6、AF10、ELL或enL)。MLL相关性白血病预后较差。一组重要的癌基因，包括同源盒A(HoxA)基因、Meis1、Flt3、MYB和MYC，在MLL相关性白血病中经常上调，并在携带MLL重排的白血病干细胞(LSCs)的自我更新中发挥关键作用。然而，临床上有意义的治疗方法还没有被开发出来有效地针对这些基因。因此，迫切需要更好地了解MLL相关白血病发病的分子机制，并在此基础上开发有效的治疗策略。MicroRNAs(MiRNA)是一类在转录后基因调控中发挥重要作用的非编码小RNA。最近，我们报道了miR-150在大多数急性髓系白血病中显著下调，其抑制在MLL-AF9介导的细胞转化和白血病发生中起关键作用；miR-150通过直接靶向Flt3/myb和间接靶向Flt3/MYB/HOXA9/Meis1在MLL-fusion/MYC/LIN28⊣miR-150⊣FLT3/MYB/HOXA9/MEIS1信号通路中发挥关键的抑癌门卫作用(蒋欣，等)。癌细胞。2012年)。假设：MIR-150对于MLL重排的AML的发展和维持以及相关LSC的自我更新都是必需的。因此，miR-150表达/功能的恢复具有很大的临床应用潜力，可用于治疗目前治疗耐药的这种类型的肿瘤 疾病。具体目的：1)确定MLL重排AML的发生和维持是否需要miR-150的抑制；2)确定MLL重排的AML的LSCs自我更新是否需要miR-150的抑制；3)确定恢复miR-150的表达/功能(通过纳米粒传递)是否是治疗MLL重排的AML的有效的新策略。研究设计：1)我们将使用小鼠骨髓移植(BMT)模型来确定异位表达miR-150是否能够显著抑制MLL重排的所有五种主要亚型AML(即MLL-AF9、-AF6、-AF10、-ELL和-ENL)的发育和维持。2)我们将进行竞争性再繁殖和限制稀释实验，以确定miR-150的异位表达是否能显著抑制相关LSCs的自我更新。3)我们将基于Flt3L(Flt3配体)导向的树枝状大分子与miR-150寡核苷酸复合，开发新型靶向纳米颗粒，并在体内外评价其在靶向/治疗MLL重排AML方面的特异性和有效性。