Genotype and phenotype of chemoresistant AML

化疗耐药性 AML 的基因型和表型

• 批准号: 8528938
• 负责人: JAMES C MULLOY
• 金额: $ 19.97万
• 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 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8528938
• 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的治疗进展是通过更好地理解该疾病的分子遗传学的。现在已经制定了新的建议，即使用与疾病相关的细胞遗传学和分子变化，这些变化影响了预后，既出于一般实践的目的，又是临床试验的标准。但是，这些分子变化对缓解诱导，复发和长期生存的影响的确切机制在大多数情况下是未知的，在每个细胞遗传学风险类别中，预后有很大的个人变化。人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屈服于化学抗性疾病。白血病研究中的一个目标是了解推动这些变异的潜在分子机制，以更好地分层患者，并对那些可以适应有针对性治疗的信号传导途径进行更多的了解。 MLL-AF9（MA9）是AML的频繁染色体异常，这是影响11q23染色体的易位的结果，并且与标准化学疗法有关的中间结果与中间结果有关。我们已经证明，该蛋白在原发性人体血液（CB）CD34+细胞中的表达诱导AML，中位潜伏期为10周。发现遗传畸变FLT3-ITD（与结果差有关）和活化的N-RAS（对患者的预后没有明显影响）均发现与人类的原发性11q23（+）样本有关。我们有数据表明，FLT3-ITD和N-RAS都与MA9有效合作，并在人类细胞中加速了白血病。我们使用AML治疗的两个主要支柱，细胞捕蛋白和阿霉素建立了一种体内诱导化疗方案，并表明我们在异种移植模型中有效靶向白血病细胞。有趣的是，MA9+FLT3-ITD白血病是对化学疗法的难治性，而MA9+N-RAS白血病是化学敏感的，在某些方面模仿了诊所中AML患者的反应。最近的数据表明，白血病异种移植实验中幸存的细胞通常是主持人类患者复发的克隆，表明异种移植方法具有识别那些在人类疾病中构成最大风险的克隆的巨大潜力。对于与化学抗性相关的特定信号级联，这些克隆的基因表达谱（GEP）可能具有很高的信息。我们假设可以确定可以预测化学治疗反应和复发潜力的签名。我们将使用原发性患者AML样品和我们自己的诱导人类AML异种移植模型来研究与治疗反应和AML失败相关的变化的化学敏感性，以确定定义的合作突变对化学耐药性的基因型贡献。这个高风险/高收益项目基于我的实验室中开发的可靠实验方法，并且具有巨大的高影响结果，并快速转化为诊所。