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

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.

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