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Project 2: Defining and exploiting genetic dependencies in complex karyotype AML

Project 2: Defining and exploiting genetic dependencies in complex karyotype AML
项目 2:定义和利用复杂核型 AML 中的遗传依赖性
批准号:
10474281
负责人:
SCOTT W. LOWE
金额:
$36.77万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-08-24 至 2026-06-30
关键词:
17pAcute Myelocytic LeukemiaAddressAnimal ModelAntitumor ResponseBiologicalCancer ModelCell LineCessation of lifeChemoresistanceChromatinChromosome abnormalityChromosomesClinicalClinical TrialsCollaborationsComplexCytogenetic AnalysisDataDeletion MutationDependenceDevelopmentDiagnosisDiseaseDisease modelDrug TargetingEnzymesEpigenetic ProcessEventFLT3 geneFaceFrequenciesGene ExpressionGeneticGenetic ModelsGenetic TranscriptionGenetically Engineered MouseGenomeGenomicsGenotypeHumanJAK2 geneKaryotypeKaryotype determination procedureKetoglutarate Dehydrogenase ComplexMalignant NeoplasmsMemorial Sloan-Kettering Cancer CenterMetabolismMethodsModelingMolecularMutationMutation AnalysisOncogenesOncogenicOncoproteinsOutcomePathogenesisPatient-Focused OutcomesPatientsPharmacologyPre-Clinical ModelPrognosisProteinsRecurrenceResearchResearch PersonnelResistanceResolutionResourcesSafetySamplingSolidSpecimenStudy modelsSystemTP53 geneTestingTherapeuticTumor Suppressor GenesTumor Suppressor ProteinsWorkactionable mutationacute myeloid leukemia cellantileukemic activitycandidate validationchemotherapychromosome 5q losscohortcostdiagnostic accuracydigitaleffective therapyexhaustionhuman diseasehuman modelimprovedinhibitorinnovationinsightleukemiamouse modelmutantnew therapeutic targetnext generation sequencingnovelnovel therapeutic interventionnovel therapeuticspatient derived xenograft modelpre-clinicalpreclinical studyprogramsself-renewalsmall molecule inhibitortherapeutic developmenttherapeutic targettherapeutically effectivetooltranscriptometranscriptome sequencingtumortumorigenicwhole genome

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中文摘要
翻译
摘要 复杂核型急性髓系白血病(CK AML)的定义是存在3个或3个以上可检测到的 细胞遗传学异常,是所有白血病基因中预后最差的基因之一。基因组学 特征表明,这种疾病缺乏传统的可用药癌蛋白,但实际上是 以TP53抑癌基因一系列反复发生的节段性缺失和突变为特征 后者在正常核型AML中缺失,并对标准化疗药物产生耐药性。至 更好地描述CK AML的发病机制,并开发治疗这种疾病的新策略,我们将 用一种新的低成本、高分辨率的方法详尽地分析大量CK AML样本的基因组 本课题组优化的平台名为“数字核型分析”。这些分子特征将与 患者结局数据,并用于生成准确概括CK AML的小鼠和人类模型- 特定功能。我们将使用这些模型来测试一种新的治疗策略,以对抗促肿瘤 P53缺失的影响。这一概念建立在初步数据的基础上,这些数据表明P53的丢失会扰乱细胞的新陈代谢。 以一种改变基因表达和驱动异常自我更新的方式,并通过 小分子抑制物可促进p53缺陷型AML的分化。具体地说,我们发现P53 突变会降低代谢物AKG的水平,产生与致癌的IDH1/2突变蛋白类似的效果 已被证明是其他亚型急性髓细胞白血病的药物靶点。在迄今研究的模型中,肿瘤抑制 P53的作用是通过抑制TCA酶2-氧戊二酸脱氢酶(OGDH)和AS来概括的 因此,我们认为OGDH是验证和开发CK AML的首选方案。成功完成 这项拟议的研究将产生对伴随CK AML的基因变化的详细了解 并允许对人类疾病进行更忠实的建模。此外,我们假设草戊二酸 脱氢酶(OGDH)是治疗CK AML的良好靶点.验证我们的新药 塔吉特将为这一适应症的临床试验铺平道路。考虑到缺乏有效的治疗选择, 对于CK AML患者,拟议的研究解决了一个紧急的、未得到满足的临床需求。
英文摘要
ABSTRACT Complex karyotype acute myeloid leukemia (CK AML) is defined by the presence of 3 or more detectable cytogenetic abnormalities and has one of the least favorable prognoses of any leukemia genotype. Genomic characterization indicates that this disease lacks conventional druggable oncoproteins, but instead is characterized by a set of recurrent segmental deletions and mutations in the TP53 tumor suppressor gene, the latter of which are absent from normal karyotype AML and confer resistance to standard chemotherapies. To better characterize the pathogenesis of CK AML and to develop new strategies to treat this disease, we will exhaustively analyze the genomes of a large cohort of CK AML samples using a new low-cost, high-resolution platform optimized in our group called “digital karyotyping”. These molecular features will be correlated with patient outcomes data, and used to generate murine and human models that accurately recapitulate CK AML- specific features. We will use these models to test a new therapeutic strategy for countering the pro-tumorigenic effects of p53 loss. This concept builds on preliminary data showing that p53 loss can perturb cellular metabolism in a manner that alters gene expression and drives aberrant self-renewal, and that reversing these effects with small molecule inhibitors can drive differentiation of p53-deficient AML. Specifically, we have found that p53 mutations reduce levels of the metabolite aKG, producing similar effects of oncogenic IDH1/2 mutant proteins that have proven to be drug targets in other sub-types of AML. In models studied to date, the tumor suppressive effects of p53 are recapitulated by inhibiting the TCA enzyme 2-oxoglutarate dehydrogenase (OGDH) and, as such, we consider OGDH a prime candidate for validation and development in CK AML. Successful completion of the proposed research will produce a detailed understanding of the genetic changes that accompany CK AML and allow for more faithful modeling of human disease. In addition, we hypothesize that oxoglutarate dehydrogenase (OGDH) a promising therapeutic target for the treatment of CK AML. Validating our novel drug target will pave the way for clinical trials in this indication. Given the paucity of effective therapeutic options for patients with CK AML, the proposed studies address an urgent, unmet clinical need.
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会议论文
Mechanisms of p53 Engagement and Action at the Benign-to-Malignant Transition in Sporadic Tumorigenesis
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Impact of the aging niche on cancer phenotypes probed using mouse cancer models produced by somatic engineering.
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