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:
- 金额:$ 33.61万
- 依托单位:
- 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:
- 关键词:Acute Myelocytic LeukemiaAcute leukemiaAddressBiological AssayBone Marrow TransplantationChimeric ProteinsChromosomal RearrangementChromosomal translocationChromosomes, Human, Pair 11ClinicClinicalCollaborationsComplementComplexDataDendrimersDevelopmentDisease ResistanceEctopic ExpressionExhibitsFLT3 geneFLT3 ligandGatekeepingGene DeliveryGene Expression RegulationGene TargetingGenerationsGenesGoalsHOXA9 geneHealthHematopathologyHematopoietic NeoplasmsHomeoboxHuman ChromosomesIn VitroInfantLeadLightMEIS1 geneMLL geneMLLT3 geneMaintenanceMalignant NeoplasmsMediatingMicroRNAsMixed-Lineage LeukemiaModelingMolecularMusNanotechnologyOligonucleotidesOncogenesPathogenesisPathway interactionsPatientsPlayPolymersReceptor Protein-Tyrosine KinasesReportingRepressionResearchResearch DesignRoleSignal TransductionSpecificitySystemTestingTherapeuticTranscriptTumor Suppressor ProteinsUntranslated RNAViralbasecancer cellcell transformationclinically significantimprovedin vivointerdisciplinary approachinterdisciplinary collaborationinterestleukemialeukemic stem cellleukemogenesismouse modelnanoparticlenovelnovel therapeutic interventionoutcome forecastoverexpressionreceptorresponserestorationself-renewalsuccesstherapy resistanttreatment 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。
项目成果
期刊论文数量(0)
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Jianjun Chen其他文献
Jianjun Chen的其他文献
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