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.

项目概要（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 (mRNA) 在许多正常生物过程中发挥作用。越来越多的证据表明 m6A 修饰中的像差和相关机制也在各种类型的 癌症。急性髓系白血病（AML）是最常见的造血系统恶性肿瘤之一，可导致多种疾病 细胞遗传学和分子异常。混合谱系白血病 (MLL) 重排 (MLLr) AML 是一种常见的 AML 的致命亚型，占“新发”AML 病例的 5%-10%，占治疗相关病例的 10%-15% 白血病（t-AML）病例。 MLLr AML 患者预后不良，总体生存期为 5 年 (OS) 率约为 30%。因此，开发改进的治疗方法迫切需要满足未满足的医疗需求。 MLLr AML 治疗。白血病干细胞/起始细胞（LSC/LIC）被认为是白血病的根本原因。 AML 治疗失败和复发。总的来说，更好地理解潜在的分子机制至关重要 MLLr AML 发病机制和 LSC/LIC 自我更新，这可能导致改进的新型治疗方法的开发 治疗 MLLr AML 的策略。我们的初步数据表明，编码 m6A 阅读器的 IGF2BP2 是专门 MLLr AML 中过度表达，其表达增加与 AML 患者的不良预后相关。 我们的初步功能研究表明 IGF2BP2 可能作为 m6A 阅读器发挥着关键的致癌作用 促进 MLLr AML 发病机制。 IGF2BP2 在 MLLr 中的表达水平也显着升高 LSC/LIC 与健康造血干/祖细胞 (HSPC) 和大量 MLLr AML 细胞相比，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，并表现出高抗白血病功效，如我们的初步结果所示 研究。 假设：IGF2BP2 在 MLLr AML 发病机制和 LSC/LIC 自我更新中发挥重要作用，并且 药物抑制 IGF2BP2 可以有效治疗 MLLr AML。 具体目标： 1) 确定IGF2BP2在MLLr AML发病机制和LSC/LIC自我更新中的作用； 2） 破译IGF2BP2在MLLr AML中作用的分子机制； 3) 评估治疗效果 药物靶向 IGF2BP2 在治疗 MLLr AML 中的潜力。 潜在影响：我们提出的研究在基础研究和研究方面都具有很高的新颖性和重要意义。 转化医学，这将大大增进我们对 MLLr 白血病生物学的理解，以及 还可能导致开发出治疗 MLLr 白血病的有效新疗法。