Genotype and phenotype of chemoresistant AML

化疗耐药性 AML 的基因型和表型

• 批准号: 8618872
• 负责人: JAMES C MULLOY
• 金额: $ 16.14万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8618872
• 关键词: 11q23; Acute; Address; Affect; Apoptosis; Automobile Driving; Back; Biological Markers; Biological Models; Categories; Cell Cycle; Cells; Chemotherapy-Oncologic Procedure; Chromosome abnormality; Clinic; Clinical; Clinical Trials; Complement; Cytarabine; Cytogenetics; Data; Data Set; Development; Disease; Disease remission; Doxorubicin; Event; Experimental Models; FLT3 gene; Failure; Frequencies; Gene Expression; Gene Expression Profile; General Practices; Genetic; Genotype; Goals; Hereditary Disease; Human; Individual; Laboratories; MLL-AF9; Modeling; Molecular; Molecular Cytogenetics; Molecular Genetics; Molecular Profiling; Mutation; N-ras Genes; Nature; Neoadjuvant Therapy; Oncogenes; Outcome; Patients; Pharmaceutical Preparations; Phenotype; Population; Recommendation; Refractory; Relapse; Remission Induction; Research; Residual state; Resistance; Risk; Sampling; Signal Pathway; Signal Transduction; Solid; Stratification; Subgroup; Surface; Testing; Tetanus Helper Peptide; Therapeutic; Time; Translating; Translations; Variant; Xenograft Model; Xenograft procedure; base; chemotherapy; cytokine; defined contribution; high risk; human cord blood CD34+ cell; human disease; in vivo; insight; leukemia; leukemogenesis; outcome forecast; prognostic; protein expression; public health relevance; research study; response

DESCRIPTION (provided by applicant): Therapeutic advances in AML have come through a better understanding of the molecular genetics of the disease. New recommendations are now in place that use disease-associated cytogenetic and molecular changes that impact outcome, both for general practice purposes as well as standards for clinical trials. However, the precise mechanisms whereby these molecular changes impact on remission induction, relapse and long-term survival are unknown for the most part, and within each cytogenetic risk category, there are large individual variations in outcome that are poorly understood. Overall outcome in human AML is still dismal, with most patients succumbing to chemoresistant disease within a relatively short time. One goal in leukemia research is to understand the underlying molecular mechanisms driving these variations, to allow better stratification of patients and to give additional insight into those signaling pathways that could be amenable to targeted therapy. MLL-AF9 (MA9) is a frequent chromosomal abnormality in AML, a result of translocations affecting chromosome 11q23, and is associated with an intermediate outcome in response to standard chemotherapy. We have demonstrated that expression of this protein in primary human cord blood (CB) CD34+ cells induces AML with a median latency of 10 weeks. The genetic aberrations FLT3-ITD (associated with a poor outcome) and activated N-ras (no clear effect on outcome in patients) are both found associated with primary 11q23(+) samples in humans. We have data showing that both FLT3-ITD and N-Ras cooperate efficiently with MA9 and accelerate leukemogenesis in human cells. We have established an in vivo induction chemotherapy regimen using the two mainstays of AML treatment, cytarabine and doxorubicin, and show that we effectively target leukemia cells in the xenograft model. Interestingly, the MA9+FLT3-ITD leukemia is refractory to chemotherapy while the MA9+N-ras leukemia is chemosensitive, mimicking in some respects the response seen in AML patients in the clinic. Recent data has demonstrated that the surviving cell in leukemia xenograft experiments is frequently the clone that presides in human patient relapse, indicating that a xenograft approach has significant potential to identify those clones that pose the greatest risk in human disease. The gene expression profiles (GEP) of these clones could be highly informative with regard to the specific signaling cascades that correlate with chemoresistance. We hypothesize that a signature can be identified that will predict chemotherapeutic response and the potential for relapse. We will use both primary patient AML samples and our own inducible human AML xenograft models to study the varying chemosensitivity associated with therapy response and failure in AML, to identify the genotypic contribution of defined cooperating mutations to chemoresistance. This high-risk/high-yield project is based on solid experimental approaches developed in my lab and has great potential for high impact findings with rapid translation to the clinic.

描述（由申请人提供）：AML的治疗进展来自于对该疾病分子遗传学的更好理解。现在的新建议是利用与疾病相关的影响结果的细胞遗传学和分子变化，既用于一般实践目的，也用于临床试验标准。然而，这些分子变化对缓解诱导、复发和长期生存影响的确切机制在很大程度上是未知的，并且在每个细胞遗传风险类别中，结果存在很大的个体差异，人们对这些差异知之甚少。人类AML的总体结果仍然令人沮丧，大多数患者在相对较短的时间内死于化疗耐药疾病。白血病研究的一个目标是了解驱动这些变异的潜在分子机制，以便更好地对患者进行分层，并对那些可能适用于靶向治疗的信号通路提供额外的见解。mml - af9 （MA9）是AML中一种常见的染色体异常，是影响11q23染色体易位的结果，与标准化疗反应的中间结果相关。我们已经证明，在原代人脐带血（CB） CD34+细胞中表达该蛋白可诱导AML，中位潜伏期为10周。基因异常FLT3-ITD（与不良预后相关）和活化的N-ras（对患者预后无明显影响）均与人类原发性11q23（+）样本相关。我们有数据表明FLT3-ITD和N-Ras都能有效地与MA9合作，加速人细胞白血病的发生。我们已经建立了一种体内诱导化疗方案，使用阿糖胞苷和阿霉素治疗AML的两种主要药物，并表明我们在异种移植模型中有效地靶向白血病细胞。有趣的是，MA9+FLT3-ITD白血病对化疗难治，而MA9+N-ras白血病对化疗敏感，在某些方面模仿临床AML患者的反应。最近的数据表明，在白血病异种移植实验中存活的细胞往往是导致人类患者复发的克隆，这表明异种移植方法有很大的潜力来识别那些对人类疾病构成最大风险的克隆。这些克隆的基因表达谱（GEP）可以提供与化学耐药相关的特定信号级联的高度信息。我们假设可以确定一种特征，可以预测化疗反应和复发的可能性。我们将使用原发患者AML样本和我们自己的可诱导的人类AML异种移植模型来研究与AML治疗反应和失败相关的不同化疗敏感性，以确定确定的合作突变对化疗耐药的基因型贡献。这个高风险/高收益的项目基于我的实验室开发的可靠的实验方法，具有快速转化为临床的高影响力发现的巨大潜力。