The role and therapeutic potential of IGF2BP2 in MLL-rearranged leukemia

IGF2BP2 在 MLL 重排白血病中的作用和治疗潜力

• 批准号: 10464855
• 负责人: Jianjun Chen
• 金额: $ 57.35万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10464855
• 关键词: Accounting; Acute Myelocytic Leukemia; Acute Promyelocytic Leukemia; Adolescent; Adult; Arsenic Trioxide; Basic Science; Binding Proteins; Biology; Cells; Childhood Leukemia; Chimeric Proteins; Chromosome abnormality; Complex; Cytogenetics; Data; Development; Exhibits; Gene Expression; Generations; Genes; Genetic Transcription; Goals; Hematopoietic Neoplasms; Hematopoietic stem cells; Knowledge; Lead; MLL-rearranged leukemia; MLLT3 gene; Maintenance; Medical; Messenger RNA; Mixed-Lineage Leukemia; Modification; Molecular; Molecular Abnormality; Oncogenic; Outcome; Pathogenesis; Pathologic; Pathway interactions; Patients; Pattern; Pharmacology; Plant Roots; Play; Prognosis; Promoter Regions; Proteins; RNA; Reader; Relapse; Role; Solid; Subgroup; Survival Rate; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Intervention; Toxic effect; Transcript; Translational Research; Translations; Treatment Efficacy; Treatment Failure; Tretinoin; acute myeloid leukemia cell; base; bioprocess; cancer type; effective therapy; improved; inhibitor; insight; leukemia; leukemia treatment; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; overexpression; pharmacokinetics and pharmacodynamics; self-renewal; side effect; small molecule inhibitor; stem; success; t(8; 21)(q22; q22); targeted treatment; therapeutically effective; translational medicine; tumor

PROJECT SUMMARY (ABSTRACT): Title: The role and therapeutic potential of IGF2BP2 in MLL-rearranged leukemia. Background: N6-methyladenosine (m6A) modification is the most abundant internal modification in eukaryotic messenger RNAs (mRNAs) and plays roles in many normal bioprocesses. Evidence is emerging that the aberration in m6A modification and the associated machinery also plays important roles in various types of cancers. Acute myeloid leukemia (AML) is one of the most common forms of hematopoietic malignancies with various cytogenetic and molecular abnormalities. The mixed-lineage leukemia (MLL)-rearranged (MLLr) AML is a common and fatal subtype of AML, which accounts for 5%-10% of “de novo” AML cases and 10%-15% of therapy-related leukemia (t-AML) cases. MLLr AML patients are associated with poor outcomes, with a 5-year overall survival (OS) rate of ~30%. Therefore, there is a critical unmet medical need to develop improved therapeutics for MLLr AML treatment. The leukemia stem/initiating cells (LSCs/LICs) are considered to be the root cause for the treatment failure and relapse of AML. Collectively, it is critical to better understand the molecular mechanisms underlying MLLr AML pathogenesis and LSC/LIC self-renewal, which may lead to the development of improved novel therapeutic strategies to treat MLLr AML. Our preliminary data showed that IGF2BP2, which encodes an m6A reader, is specially overexpressed in MLLr AML and its increased expression is associated with a poor prognosis in AML patients. Our preliminary functional studies suggest that IGF2BP2 likely plays a critical oncogenic role as an m6A reader in promoting MLLr AML pathogenesis. IGF2BP2 is also expressed at a significantly higher level in MLLr LSCs/LICs compared to healthy hematopoietic stem/progenitor cells (HSPCs) and bulk MLLr AML cells, implying a role of IGF2BP2 in MLLr LSC/LIC self-renewal. In addition, we have developed a potent inhibitor (namely CWI1-2) that targets IGF2BP2 directly and exhibits high anti-leukemia efficacy as shown in our preliminary studies. Hypothesis: IGF2BP2 plays an essential role in MLLr AML pathogenesis and LSC/LIC self-renewal, and that pharmacological inhibition of IGF2BP2 can lead to effective treatment of MLLr AML. Specific Aims: 1) Determine the role of IGF2BP2 in MLLr AML pathogenesis and LSC/LIC self-renewal; 2) Decipher the molecular mechanism underlying the role of IGF2BP2 in MLLr AML; and 3) Assess the therapeutic potential of pharmacologically targeting IGF2BP2 in treating MLLr AML. Potential Impact: Our proposed studies are of high novelty and high significance in both basic research and translational medicine, which will substantially advance our understanding of the biology of MLLr leukemia, and may also result in the development of effective novel therapeutics for the treatment of MLLr leukemia.

项目摘要(摘要)： 标题：IGF2BP2在MLL重排白血病中的作用和治疗潜力。 背景：N6-甲基腺苷(M6A)修饰是最丰富的内部修饰 真核生物信使RNA(MRNAs)，在许多正常的生物过程中发挥作用。越来越多的证据表明 M6A修饰中的像差及其相关机制在各种类型的白血病中也起着重要作用 癌症。急性髓系白血病(AML)是最常见的血液系统恶性肿瘤之一，具有多种类型 细胞遗传学和分子异常。混合系白血病(MLL)-重排(MLLr)AML是一种常见的 和致命性AML亚型，占初治AML病例的5%-10%，占与治疗相关的10%-15% 白血病(t-AML)病例。MLLr AML患者预后较差，总生存期为5年 (OS)率约30%。因此，有一个迫切的未得到满足的医学需求，即开发改进的治疗方法 MLLr AML治疗。白血病干细胞/起始细胞(LSCs/LICs)被认为是导致 急性髓系白血病治疗失败和复发。总的来说，更好地理解潜在的分子机制是至关重要的。 MLLr AML的发病机制和LSC/LIC的自我更新可能导致改进的新治疗方法的开发 治疗MLLr AML的策略。我们的初步数据显示，编码M6A阅读器的IGF2BP2是一种特殊的 MLLr在AML中高表达，其表达增强与AML患者预后不良相关。 我们的初步功能研究表明，IGF2BP2可能作为m6A阅读器发挥关键的致癌作用 在促进MLLr AML发病机制中发挥重要作用。IGF2BP2在MLLr中的表达水平也显著高于MLLr LSCs/LICs与健康的造血干/祖细胞(HSPC)和大量MLLr AML细胞的比较，这意味着 IGF2BP2在MLLr LSC/LIC自我更新中的作用此外，我们还开发了一种有效的抑制剂(即 CWI1-2)直接靶向IGF2BP2，并显示出较高的抗白血病效果 学习。 假设：IGF2BP2在MLLr AML发病和LSC/LIC自我更新中起重要作用 药物抑制IGF2BP2可有效治疗MLLr AML。 特异性目的：1)确定IGF2BP2在MLLr AML发病机制和LSC/LIC自我更新中的作用； 破译IGF2BP2在MLLr AML中作用的分子机制；3)评估治疗 药物靶向IGF2BP2治疗MLLr AML的潜力 潜在影响：我们提出的研究具有很高的新颖性，在基础研究和 转化医学，这将极大地促进我们对MLLr白血病生物学的了解，以及 也可能导致开发有效的治疗MLLr白血病的新疗法。