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: 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
• 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

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，包括同源框 A (HOXA) 基因、MEIS1、FLT3、MYB 和 MYC，在 MLL 相关白血病中经常上调，并在携带 MLL 重排的白血病干细胞 (LSC) 的自我更新中发挥关键作用。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、-AF6、-AF10、-ELL和-ENL）的发育和维持。 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。