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: 10579300
• 负责人: Jianjun Chen
• 金额: $ 56.21万
• 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/10579300
• 关键词: Accounting; Acute Myelocytic Leukemia; Acute Promyelocytic Leukemia; Adolescent; 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; MLLT3 gene; Maintenance; Medical; Messenger RNA; Mixed-Lineage Leukemia; Modification; Molecular; Molecular Abnormality; Oncogenic; Outcome; Pathogenesis; Pathologic; Pathway interactions; Patients; Pattern; Play; Prognosis; Promoter Regions; Proteins; RNA; Reader; Relapse; Role; Solid Neoplasm; Subgroup; Survival Rate; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Intervention; Toxic effect; Transcript; Translational Research; Translations; Treatment Efficacy; Treatment Failure; Tretinoin; Tumor Promotion; acute myeloid leukemia cell; adult leukemia; bioprocess; cancer type; effective therapy; improved; inhibitor; insight; leukemia; leukemia treatment; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; overexpression; pharmacokinetics and pharmacodynamics; pharmacologic; posttranscriptional; self-renewal; side effect; small molecule inhibitor; stem; success; t(8; 21)(q22; q22); targeted treatment; therapeutically effective; translational medicine; Accounting; Acute Myelocytic Leukemia; Acute Promyelocytic Leukemia; Adolescent; 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; MLLT3 gene; Maintenance; Medical; Messenger RNA; Mixed-Lineage Leukemia; Modification; Molecular; Molecular Abnormality; Oncogenic; Outcome; Pathogenesis; Pathologic; Pathway interactions; Patients; Pattern; Play; Prognosis; Promoter Regions; Proteins; RNA; Reader; Relapse; Role; Solid Neoplasm; Subgroup; Survival Rate; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Intervention; Toxic effect; Transcript; Translational Research; Translations; Treatment Efficacy; Treatment Failure; Tretinoin; Tumor Promotion; acute myeloid leukemia cell; adult leukemia; bioprocess; cancer type; effective therapy; improved; inhibitor; insight; leukemia; leukemia treatment; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; overexpression; pharmacokinetics and pharmacodynamics; pharmacologic; posttranscriptional; self-renewal; side effect; small molecule inhibitor; stem; success; t(8; 21)(q22; q22); targeted treatment; therapeutically effective; translational medicine

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重新培养的白血病中的作用和治疗潜力。 背景：N6-甲基趋化胺（M6A）修饰是最丰富的内部修饰 真核生物信使RNA（mRNA）在许多正常的生物过程中扮演角色。有证据表明 M6A修饰和相关机械的畸变也在各种类型的 癌症。急性髓样白血病（AML）是造血恶性肿瘤的最常见形式之一 细胞遗传学和分子异常。混合赛的白血病（MLL） - 重新安排（MLLR）AML是一个常见 AML的致命亚型，占“从头” AML病例的5％-10％，与治疗相关的10％-15％ 白血病（T-AML）病例。 MLLR AML患者与结果不佳有关，总生存率为5年 （OS）率〜30％。因此，有至关重要的医疗需要开发改进的治疗 MLLR AML处理。白血病/启动细胞（LSC/LIC）被认为是根本原因 治疗失败和AML的缓解。总的来说，更好地了解基本机制的分子机制至关重要 MLLR AML发病机理和LSC/LIC自我更新，这可能导致改进的新型治疗 治疗MLLR AML的策略。我们的初步数据表明，编码M6A读取器的IGF2BP2是特别的 MLLR AML过表达，其表达增加与AML患者的预后不良有关。 我们的初步功能研究表明，IGF2BP2可能在M6A读取器中起关键的致癌作用 在促进MLLR AML发病机理中。在MLLR中，IGF2BP2也以明显更高的水平表达 LSC/LIC与健康的造血干/祖细胞（HSPC）和大量MLLR AML细胞相比 IGF2BP2在MLLR LSC/LIC自我更新中的角色。此外，我们已经开发了潜在的抑制剂（即 CWI1-2）直接靶向IGF2BP2并表现出高抗白血病效率，如我们的初步所示 研究。 假设：IGF2BP2在MLLR AML发病机理和LSC/LIC自我更新中起着至关重要的作用，并且 对IGF2BP2的药物抑制作用可有效治疗MLLR AML。 具体目的：1）确定IGF2BP2在MLLR AML发病机理和LSC/LIC自我更新中的作用； 2） 破译IGF2BP2在MLLR AML中的作用的分子机制； 3）评估疗法 药物在处理MLLR AML中靶向IGF2BP2的潜力。 潜在的影响：我们提出的研究在基础研究和 转化医学将大大提高我们对MLLR白血病生物学的理解，并 也可能导致有效的新型治疗MLLR白血病。