Biologic and therapeutic relevance of DNMT3A mutations in acute myeloid leukemia
急性髓系白血病 DNMT3A 突变的生物学和治疗相关性
基本信息
- 批准号:8567405
- 负责人:
- 金额:$ 9.79万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-08-07 至 2015-07-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaAddressAdoptive TransferAffectAffinityAllelesAmino AcidsApoptosisApoptoticAwardBindingCellsChIP-seqClinicClinical OncologyCritiquesCytotoxic agentDNADNA BindingDNA DamageDNA MethylationDNA MethyltransferaseDNA Modification MethylasesDevelopmentDiagnosticDimerizationDiseaseDissociationExhibitsFailureFamilyGene ExpressionGenesGeneticGenomic InstabilityGenotoxic StressGoalsHematopoiesisHematopoieticHematopoietic NeoplasmsIn VitroIndividualKnock-in MouseMalignant - descriptorMalignant NeoplasmsMediatingMedicineMentorsMolecularMutationMyelogenousOncogene ActivationOutcomePathogenesisPathway interactionsPatientsPatternPhasePhenotypePlayPopulationPropertyReactive Oxygen SpeciesRecurrenceRecurrent diseaseResearchResearch ProposalsResistanceResistance developmentRoleSamplingSeriesSomatic MutationSpecificityStagingStem cellsStressTherapeuticTimeTranslatingWorkWritingadverse outcomeanticancer researchattenuationbasecancer therapycareerchemotherapydesigngenome sequencinggenome wide methylationimprovedin vivoin vivo Modelinsightirradiationleukemialeukemogenesismeetingsmouse modelmutantnovelpre-clinicalpreclinical studyprognosticpublic health relevancerepairedresearch studyresponseself-renewalstemtherapeutic developmenttranslational study
项目摘要
DESCRIPTION (provided by applicant): Biologic and therapeutic relevance of DNMT3A mutations in acute myeloid leukemia Despite the many new advances in cancer research and treatment, therapeutic resistance remains the core challenge in clinical oncology. Genome sequencing efforts have made possible the identification of genes and specific mutations associated with therapeutic failure in the clinic. However, the molecular basis of therapeutic resistance remains largely enigmatic. Recurrent DNMT3A mutations are detected in 25-30% of acute myeloid leukemia (AML) patients and are associated with adverse outcome and resistance to frontline chemotherapy. DNMT3A mutations most often affect amino acid residue R882, and recent work has shown that these mutants display decreased enzymatic activity and aberrant binding properties. In addition, previous studies have shown that increased expression of DNMT3A functions as a pro-apoptotic switch in response to genotoxic stress. We hypothesized that DNMT3A mutations protect cells from apoptosis in response to DNA damage caused by oncogene activation, or by ionizing irradiation (IR) or chemotherapeutics, allowing for the survival of malignant hematopoietic cells. Our preliminary studies show that expression of the AML-associated DNMT3A mutants in primary hematopoietic cells inhibits myeloid differentiation, with accumulation of stem/progenitor cells, reduces apoptosis and increases self-renewal in vitro. In addition, cells harboring mutant DNMT3A exhibited hallmarks of genomic instability. Our mechanistic studies point at impaired DNA damage response including attenuation of p53 activation. This research proposal outlines a three-tiered approach to the comprehensive characterization of the role for DNMT3A mutations in normal and leukemic hematopoiesis and therapeutic resistance. First, we will use adoptive transfer approach in vivo studies and ex vivo studies to assess the contribution of leukemia-associated DNMT3A mutants to alterations in differentiation, apoptosis, and self-renewal in different stem/progenitor cell populations. Next, the molecular mechanisms underlying etiologic role of mutant DNMT3A in AML pathogenesis will be explored. We will address the changes in DNA methylation patterns and DNA binding in DNMT3A-mutant cells through genome-wide methylation profiling and ChIP-seq studies, and perform detailed analysis of DNA damage sensing, response and repair in cells with and without DNMT3A mutations. These studies will be initiated during the mentored phase, and will continue into the independent stage of the award, when the main focus will shift to pre-clinical development of mechanistically-informed anti-leukemic treatments. These functional, mechanistic and pre-clinical studies will be carried out in a novel genetic mouse model expressing leukemia-associated Dnmt3a mutant from its native locus. Overall we posit that genetic alterations in the DNMT3A gene play an important role in development of AML in many patients, and a more thorough understanding of this phenomenon is likely to have eventual diagnostic, prognostic and therapeutic implications.
描述(由申请人提供):急性髓性白血病中DNMT 3A突变的生物学和治疗相关性尽管癌症研究和治疗取得了许多新进展,但治疗耐药性仍然是临床肿瘤学的核心挑战。基因组测序的努力已经使得在临床上识别与治疗失败相关的基因和特定突变成为可能。然而,耐药性的分子基础在很大程度上仍然是个谜。复发性DNMT 3A突变在25-30%的急性髓性白血病(AML)患者中检测到,并与不良结局和一线化疗耐药性相关。DNMT 3A突变最常影响氨基酸残基R882,最近的工作表明,这些突变体显示出降低的酶活性和异常的结合特性。此外,先前的研究已经表明,DNMT 3A的表达增加作为响应于遗传毒性应激的促凋亡开关起作用。我们假设DNMT 3A突变保护细胞免于细胞凋亡,以响应由癌基因激活或电离辐射(IR)或化疗剂引起的DNA损伤,从而允许恶性造血细胞存活。我们的初步研究表明,AML相关的DNMT 3A突变体在原代造血细胞中的表达抑制骨髓分化,伴随干/祖细胞的积累,减少细胞凋亡并增加体外自我更新。此外,携带突变体DNMT 3A的细胞表现出基因组不稳定性的标志。我们的机制研究指出,在受损的DNA损伤反应,包括p53激活的衰减。这项研究计划概述了一个三层的方法来全面表征DNMT 3A突变在正常和白血病造血和治疗耐药性中的作用。首先,我们将使用过继转移的方法在体内研究和离体研究,以评估白血病相关的DNMT 3A突变体的分化,凋亡和自我更新在不同的干/祖细胞群的改变的贡献。接下来,将探索突变体DNMT 3A在AML发病机制中的病因作用的分子机制。我们将通过全基因组甲基化分析和ChIP-seq研究来解决DNMT 3A突变细胞中DNA甲基化模式和DNA结合的变化,并对有和没有DNMT 3A突变的细胞中的DNA损伤传感,反应和修复进行详细分析。这些研究将在指导阶段启动,并将继续进入该奖项的独立阶段,届时主要重点将转移到临床前开发机械知情的抗白血病治疗。这些功能、机制和临床前研究将在从其天然基因座表达白血病相关Dnmt 3a突变体的新型遗传小鼠模型中进行。总的来说,我们认为DNMT 3A基因的遗传改变在许多患者的AML发展中起着重要作用,对这种现象的更深入了解可能具有最终的诊断,预后和治疗意义。
项目成果
期刊论文数量(0)
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Olga A Guryanova其他文献
NPM1 Mutation Reprograms Leukemic Transcription Network Via Reshaping CTCF-Defined TAD Topology
- DOI:
10.1182/blood-2022-160367 - 发表时间:
2022-11-15 - 期刊:
- 影响因子:
- 作者:
Karina Hamamoto;Qian Lai;Huacheng Luo;Julia Lesperance;Zachary Zaroogian;Jie Zha;Yi Qiu;Olga A Guryanova;Bing Xu;Suming Huang - 通讯作者:
Suming Huang
3015 – CLONAL HEMATOPOIESIS DRIVEN BY PARTIAL DNMT3A LOSS CONTRIBUTES TO AN AGGRESSIVE PHENOTYPE OF COLITIS-ASSOCIATED COLON CANCER
- DOI:
10.1016/j.exphem.2021.12.237 - 发表时间:
2021-08-01 - 期刊:
- 影响因子:
- 作者:
Olga A Guryanova;Yang Feng;Rachel Newsome;Troy Robinson;Robert Bowman;Ashley Zuniga;Kendra Hall;Cassandra Berntsen;Daniil Shabashvili;Ross Levine;Alberto Riva;Christian Jobin;Dorina Avram - 通讯作者:
Dorina Avram
Study of the Dynamics and Diversity of Hematopoietic Stem Cells during Aging and Senolytic Drug Treatment Using Single Cell Transcriptomics
- DOI:
10.1182/blood-2022-170033 - 发表时间:
2022-11-15 - 期刊:
- 影响因子:
- 作者:
Bowen Yan;Guangrong Zheng;Daohong Zhou;Olga A Guryanova - 通讯作者:
Olga A Guryanova
Olga A Guryanova的其他文献
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{{ truncateString('Olga A Guryanova', 18)}}的其他基金
The role of DNMT3A mutations in clonal heterogeneity and evolution of hematopoiesis
DNMT3A 突变在克隆异质性和造血进化中的作用
- 批准号:
9977184 - 财政年份:2019
- 资助金额:
$ 9.79万 - 项目类别:
The role of DNMT3A mutations in clonal heterogeneity and evolution of hematopoiesis
DNMT3A 突变在克隆异质性和造血进化中的作用
- 批准号:
10617235 - 财政年份:2019
- 资助金额:
$ 9.79万 - 项目类别:
The role of DNMT3A mutations in clonal heterogeneity and evolution of hematopoiesis
DNMT3A 突变在克隆异质性和造血进化中的作用
- 批准号:
10398064 - 财政年份:2019
- 资助金额:
$ 9.79万 - 项目类别:
Biologic and therapeutic relevance of DNMT3A mutations in acute myeloid leukemia
急性髓系白血病 DNMT3A 突变的生物学和治疗相关性
- 批准号:
9320627 - 财政年份:2016
- 资助金额:
$ 9.79万 - 项目类别:
Biologic and therapeutic relevance of DNMT3A mutations in acute myeloid leukemia
急性髓系白血病 DNMT3A 突变的生物学和治疗相关性
- 批准号:
9352281 - 财政年份:2016
- 资助金额:
$ 9.79万 - 项目类别:
Biologic and therapeutic relevance of DNMT3A mutations in acute myeloid leukemia
急性髓系白血病 DNMT3A 突变的生物学和治疗相关性
- 批准号:
8716708 - 财政年份:2013
- 资助金额:
$ 9.79万 - 项目类别:
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