Identifying the spectrum of genetic alterations in high risk ALL

描述（由申请人提供）：本项目的目标是使用当代基因组分析方法来鉴定导致高危急性白血病发病机制和治疗结果的遗传改变。尽管目前有最好的治疗方法，但急性淋巴细胞白血病仍然是年轻人癌症相关死亡的主要原因，在成年人中通常结局不佳。针对合理的治疗靶点的新疗法是改善高危白血病预后的迫切需要。我们最近的基因组分析已经确定了一些新的突变，这些突变靶向ALL中的关键细胞生长和分化途径，这些途径有助于白血病的发生，预测结果，并作为新疗法的靶点。然而，对几种高危白血病亚型的遗传基础仍知之甚少，包括BCR-ABL 1（费城染色体）阳性白血病、低亚二倍体ALL和缺乏复发性细胞遗传学改变的B祖细胞ALL病例。BCR-ABL 1是慢性粒细胞白血病的标志，也是急性白血病的一个亚类，但决定BCR-ABL 1疾病谱系、疾病进展和治疗反应的遗传改变却知之甚少。低亚二倍体-多个完整染色体的丢失-与ALL的预后非常差相关，但直到最近，这种疾病的详细基因组分析一直缺乏。此外，尽管我们对ALL遗传学的理解最近取得了进展，但仍有相当一部分病例缺乏复发性细胞遗传学改变，治疗失败，这些病例的耐药基础尚不清楚。更好地了解这些疾病的关键障碍是缺乏大量具有详细临床数据的患者样本，以及缺乏高分辨率的全基因组平台来全面识别癌症中的所有遗传变异。在这里，我们将使用互补的基因组分析方法，包括微阵列分析的增益和损失的DNA，候选基因重测序，和下一代测序的肿瘤细胞RNA（“转录组重测序”），以确定这些疾病的遗传改变，并检查与治疗结果和疾病进展的关联。这些基因组研究将通过对白血病细胞内信号通路的遗传改变的影响进行详细的实验分析来补充。总之，这些方法提供了一个重要的机会，以提高我们的理解和治疗结果的一些临床上最有问题的类型的白血病。 公共卫生相关性：该项目将使用尖端的基因组技术来检查几种高危白血病的遗传基础。急性淋巴细胞白血病（ALL）是最常见的儿童癌症。尽管总体治愈率良好，但治疗失败和复发ALL仍然是儿童癌症死亡的主要原因。我们最近在ALL中的基因组分析研究已经证明了这些方法在发现与疾病发展相关的白血病新遗传改变以及预测治疗结果和确定新治疗靶点的变化方面的能力。几种复发风险高的白血病亚型的研究仍然很少。本项目将检查携带费城染色体（BCR-ABL 1）的白血病、低亚二倍体ALL和常规细胞遗传学分析缺乏变化的ALL病例。我们的目标是检测新的遗传变化，并检查遗传变化和治疗结果之间的关联。该项目将使用成熟的基因组分析方法（微阵列和测序）以及新的方法-转录组重测序-以识别改变癌细胞中蛋白质的所有突变。这些研究提供了一个重要的机会，以更好地了解癌症的遗传基础，仍然是年轻人的主要问题。最终，这些信息将有助于开发更好的癌症治疗方法。

DESCRIPTION (provided by applicant): The goal of this project is to use contemporary genomic profiling approaches to identify genetic alterations contributing to the pathogenesis and treatment outcome of high risk acute leukemia. Despite best current therapy, acute lymphoblastic leukemia remains a leading cause of cancer- related death in young people, and commonly has a poor outcome in adults. New treatments directed against rational therapeutic targets are urgently required to improve the outcome of high risk leukemia. Our recent genomic analyses have identified a number of new mutations targeting key cellular growth and differentiation pathways in ALL that contribute to the leukemogenesis, predict outcome, and serve as targets for novel therapies. However, the genetic basis of several subtypes of high-risk leukemia remains poorly understood, including BCR-ABL1 (Philadelphia chromosome) positive leukemia, ALL with low hypodiploidy, and B- progenitor ALL cases lacking recurring cytogenetic alterations. BCR-ABL1 is a hallmark of chronic myeloid leukemia and a subset of acute leukemia, but the genetic alterations that determine the lineage of BCR-ABL1 disease, disease progression and response to therapy are poorly understood. Low hypodiploidy - the loss of multiple whole chromosomes - is associated with very poor outcome in ALL, but until recently detailed genomic analyses of this disease have been lacking. Furthermore, despite recent advances in our understanding of the genetics of ALL, a substantial minority of cases lack recurring cytogenetic alterations and fail therapy, and the basis of resistance to treatment in these cases is unknown. The key barriers to a better understanding of these conditions have been the lack of large cohorts of patient samples with detailed clinical data, and the lack of high-resolution, genome-wide platforms to comprehensively identify all genetic alterations in cancer. Here we will use complementary genomic profiling approaches, including microarray analysis of gains and losses of DNA, candidate gene resequencing, and next generation sequencing of tumor cell RNA ("transcriptomic resequencing") to identify genetic alterations in these diseases, and to examine associations with treatment outcome and disease progression. These genomic studies will be complemented by detailed experimental analysis of the effect of genetic alterations on signaling pathways within leukemic cells. Together, these approaches offer an important opportunity to improve our understanding and the treatment outcome of some of the clinically most problematic types of leukemia. PUBLIC HEALTH RELEVANCE: This project will use cutting-edge genomic technologies to examine the genetic basis of several types of high- risk leukemia. Acute lymphoblastic leukemia (ALL) is the commonest childhood cancer. Despite favorable overall cure rates, treatment failure and relapse ALL remains a leading cause of childhood cancer death. Our recent genomic profiling studies in ALL have demonstrated the power of these approaches to find new genetic alterations in leukemia that are associated with the development of the disease, and changes that predict treatment outcome and identify new targets for therapy. Several leukemia subtypes that have a high risk of relapse remain poorly studied. This project will examine leukemias harboring the Philadelphia chromosome (BCR-ABL1), low hypodiploid ALL, and ALL cases lacking changes on conventional cytogenetic analysis. We aim to detect new genetic changes, and also examine associations between genetic changes and treatment outcome. This project will use both well-established genomic profiling approaches (microarrays and sequencing) together with novel approaches - transcriptomic resequencing - with the goal of identifying all mutations that change proteins in a cancer cell. These studies offer an important opportunity to better understand the genetic basis of cancers that remain major problems in young people. Ultimately, this information will help the development of improved therapies for cancer.