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: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-24 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10474281
• 关键词: 17p; Acute Myelocytic Leukemia; Address; Animal Model; Antitumor Response; Biological; Cancer Model; Cell Line; Cessation of life; Chemoresistance; Chromatin; Chromosome abnormality; Chromosomes; Clinical; Clinical Trials; Collaborations; Complex; Cytogenetic Analysis; Data; Deletion Mutation; Dependence; Development; Diagnosis; Disease; Disease model; Drug Targeting; Enzymes; Epigenetic Process; Event; FLT3 gene; Face; Frequencies; Gene Expression; Genetic; Genetic Models; Genetic Transcription; Genetically Engineered Mouse; Genome; Genomics; Genotype; Human; JAK2 gene; Karyotype; Karyotype determination procedure; Ketoglutarate Dehydrogenase Complex; Malignant Neoplasms; Memorial Sloan-Kettering Cancer Center; Metabolism; Methods; Modeling; Molecular; Mutation; Mutation Analysis; Oncogenes; Oncogenic; Oncoproteins; Outcome; Pathogenesis; Patient-Focused Outcomes; Patients; Pharmacology; Pre-Clinical Model; Prognosis; Proteins; Recurrence; Research; Research Personnel; Resistance; Resolution; Resources; Safety; Sampling; Solid; Specimen; Study models; System; TP53 gene; Testing; Therapeutic; Tumor Suppressor Genes; Tumor Suppressor Proteins; Work; actionable mutation; acute myeloid leukemia cell; antileukemic activity; candidate validation; chemotherapy; chromosome 5q loss; cohort; cost; diagnostic accuracy; digital; effective therapy; exhaustion; human disease; human model; improved; inhibitor; innovation; insight; leukemia; mouse model; mutant; new therapeutic target; next generation sequencing; novel; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; pre-clinical; preclinical study; programs; self-renewal; small molecule inhibitor; therapeutic development; therapeutic target; therapeutically effective; tool; transcriptome; transcriptome sequencing; tumor; tumorigenic; whole genome

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.

摘要 复杂核型急性髓细胞白血病（CK AML）是指存在3个或更多可检测的 细胞遗传学异常，并且具有任何白血病基因型中最不利的遗传学特征之一。基因组 表征表明，这种疾病缺乏常规的可药物化的癌蛋白，而是 其特征在于TP 53肿瘤抑制基因中的一组复发性节段性缺失和突变， 后者在正常核型AML中不存在，并赋予对标准化疗的抗性。到 为了更好地描述CK AML的发病机制并开发治疗这种疾病的新策略，我们将 使用新的低成本，高分辨率， 在我们的小组中优化的平台称为“数字核型分析”。这些分子特征将与 患者结果数据，并用于生成准确概括CK AML的鼠和人模型- 具体特点。我们将使用这些模型来测试一种新的治疗策略， 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的缺失会扰乱细胞代谢。 以改变基因表达和驱动异常自我更新的方式， 小分子抑制剂可以驱动p53缺陷型AML的分化。我们发现，p53 突变降低代谢物aKG的水平，产生与致癌IDH 1/2突变蛋白相似的作用 已经被证明是其他AML亚型的药物靶点。在迄今为止研究的模型中， p53的作用通过抑制TCA酶2-酮戊二酸脱氢酶（OGDH）而重现， 因此，我们认为OGDH是在CK AML中验证和开发主要候选者。成功完成 这项拟议中的研究将详细了解伴随CK AML的遗传变化， 并允许对人类疾病进行更忠实的建模。此外，我们假设酮戊二酸 脱氢酶（OGDH）是治疗CK AML的有希望的治疗靶点。验证我们的新药 Target将为该适应症的临床试验铺平道路。由于缺乏有效的治疗选择， 对于CK AML患者，拟定的研究解决了一个紧迫的、未满足的临床需求。