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
- 来源:
- 关键词:AccountingAcute Myelocytic LeukemiaAcute Promyelocytic LeukemiaAdolescentAdultArsenic TrioxideBasic ScienceBinding ProteinsBiologyCellsChildhood LeukemiaChimeric ProteinsChromosome abnormalityComplexCytogeneticsDataDevelopmentExhibitsGene ExpressionGenerationsGenesGenetic TranscriptionGoalsHematopoietic NeoplasmsHematopoietic stem cellsKnowledgeLeadMLL-rearranged leukemiaMLLT3 geneMaintenanceMedicalMessenger RNAMixed-Lineage LeukemiaModificationMolecularMolecular AbnormalityOncogenicOutcomePathogenesisPathologicPathway interactionsPatientsPatternPharmacologyPlant RootsPlayPrognosisPromoter RegionsProteinsRNAReaderRelapseRoleSolidSubgroupSurvival RateTestingTherapeuticTherapeutic AgentsTherapeutic EffectTherapeutic InterventionToxic effectTranscriptTranslational ResearchTranslationsTreatment EfficacyTreatment FailureTretinoinacute myeloid leukemia cellbasebioprocesscancer typeeffective therapyimprovedinhibitorinsightleukemialeukemia treatmentnew therapeutic targetnovelnovel therapeutic interventionnovel therapeuticsoverexpressionpharmacokinetics and pharmacodynamicsself-renewalside effectsmall molecule inhibitorstemsuccesst(821)(q22q22)targeted treatmenttherapeutically effectivetranslational medicinetumor
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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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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