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

基本信息

  • 批准号:
    10464855
  • 负责人:
  • 金额:
    $ 57.35万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
项目总结(摘要): IGF 2BP 2在MLL重排白血病中的作用和治疗潜力 背景:N6-甲基腺苷(m6 A)修饰是细胞内最丰富的内部修饰, 真核生物的信使RNA(mRNA),并在许多正常的生物过程中发挥作用。有证据表明, m6 A修饰和相关机制中的畸变在各种类型的 癌的急性髓性白血病(AML)是最常见的造血系统恶性肿瘤形式之一,具有各种不同的病理改变。 细胞遗传学和分子异常。混合系白血病(MLL)重排(MLLR)AML是一种常见的白血病 和致死性AML亚型,占“新发”AML病例的5%-10%,占治疗相关AML病例的10%-15%。 白血病(t-AML)病例。MLLr AML患者结局较差,5年总生存期 (OS)率约30%。因此,存在关键的未满足的医学需求,以开发用于治疗糖尿病的改进的治疗剂。 MLLr AML治疗。白血病干/起始细胞(LSC/LIC)被认为是白血病的根本原因。 治疗失败和AML复发。总的来说,更好地了解其背后的分子机制至关重要。 MLLR AML发病机制和LSC/LIC自我更新,这可能导致开发改进的新治疗药物。 治疗MLLR AML的策略。我们的初步数据显示,编码m6 A阅读器的IGF 2BP 2是特异性的, 在MLLr AML中过表达,并且其表达增加与AML患者的不良预后相关。 我们的初步功能研究表明,IGF 2BP 2可能作为m6 A阅读器发挥关键的致癌作用 促进MLLR AML发病。IGF 2BP 2在MLLR中也以显着更高的水平表达 LSC/LIC与健康造血干/祖细胞(HSPC)和大量MLLR AML细胞相比, IGF 2BP 2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 CWI 1 -2),其直接靶向IGF 2BP 2并表现出高抗白血病功效,如我们的初步研究所示。 问题研究 假设:IGF 2BP 2在MLLR AML发病机制和LSC/LIC自我更新中起重要作用, IGF 2BP 2的药理学抑制可导致MLLr AML的有效治疗。 具体目的:1)确定IGF 2BP 2在MLLR AML发病机制和LSC/LIC自我更新中的作用; 2) 解读IGF 2BP 2在MLLR AML中作用的分子机制;以及3)评估治疗性IGF 2BP 2的疗效。 靶向IGF 2BP 2的AML治疗MLLR AML的潜力。 潜在影响:我们提出的研究具有高度的新奇,在基础研究和 转化医学,这将大大促进我们对MLLR白血病生物学的理解, 也可能导致开发用于治疗MLLR白血病的有效的新疗法。

项目成果

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Jianjun Chen其他文献

Jianjun Chen的其他文献

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{{ truncateString('Jianjun Chen', 18)}}的其他基金

TET2-mediated epitranscriptomic regulation in leukemia microenvironment
TET2介导的白血病微环境中的表观转录组调控
  • 批准号:
    10801348
  • 财政年份:
    2023
  • 资助金额:
    $ 57.35万
  • 项目类别:
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
  • 财政年份:
    2022
  • 资助金额:
    $ 57.35万
  • 项目类别:
The function and underlying mechanism of TET1 in myelodysplastic syndromes
TET1在骨髓增生异常综合征中的功能及机制
  • 批准号:
    10549295
  • 财政年份:
    2020
  • 资助金额:
    $ 57.35万
  • 项目类别:
The function and underlying mechanism of TET1 in myelodysplastic syndromes
TET1在骨髓增生异常综合征中的功能及机制
  • 批准号:
    10304942
  • 财政年份:
    2020
  • 资助金额:
    $ 57.35万
  • 项目类别:
The function and underlying mechanism of TET1 in myelodysplastic syndromes
TET1在骨髓增生异常综合征中的功能及机制
  • 批准号:
    9914855
  • 财政年份:
    2020
  • 资助金额:
    $ 57.35万
  • 项目类别:
The role and mechanism of METTL3/METTL14-mediated RNA modification in the pathogenesis and drug-resistance of AML
METTL3/METTL14介导的RNA修饰在AML发病及耐药中的作用及机制
  • 批准号:
    10329928
  • 财政年份:
    2019
  • 资助金额:
    $ 57.35万
  • 项目类别:
Targeting FTO to treat acute myeloid leukemia
靶向FTO治疗急性髓系白血病
  • 批准号:
    10058254
  • 财政年份:
    2019
  • 资助金额:
    $ 57.35万
  • 项目类别:
Targeting FTO to treat acute myeloid leukemia
靶向FTO治疗急性髓系白血病
  • 批准号:
    10531853
  • 财政年份:
    2019
  • 资助金额:
    $ 57.35万
  • 项目类别:
The role and mechanism of METTL3/METTL14-mediated RNA modification in the pathogenesis and drug-resistance of AML
METTL3/METTL14介导的RNA修饰在AML发病及耐药中的作用及机制
  • 批准号:
    9765111
  • 财政年份:
    2019
  • 资助金额:
    $ 57.35万
  • 项目类别:
The role and mechanism of METTL3/METTL14-mediated RNA modification in the pathogenesis and drug-resistance of AML
METTL3/METTL14介导的RNA修饰在AML发病及耐药中的作用及机制
  • 批准号:
    10558640
  • 财政年份:
    2019
  • 资助金额:
    $ 57.35万
  • 项目类别:

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