PDF(Pubmed)
Abstract：
Acute leukemia is a particularly problematic collection of hematological cancers, and, while somewhat rare, the survival rate of patients is typically abysmal without bone marrow transplantation. Furthermore, traditional chemotherapies used as standard-of-care for patients cause significant side effects. Understanding the evolution of leukemia to identify novel targets and, therefore, drug treatment regimens is a significant medical need. Genomic rearrangements and other structural variations (SVs) have long been known to be causative and pathogenic in multiple types of cancer, including leukemia. These SVs may be involved in cancer initiation, progression, clonal evolution, and drug resistance, and a better understanding of SVs from individual patients may help guide therapeutic options. Here, we show the utilization of optical genome mapping (OGM) to detect known and novel SVs in the samples of patients with leukemia. Importantly, this technology provides an unprecedented level of granularity and quantitation unavailable to other current techniques and allows for the unbiased detection of novel SVs, which may be relevant to disease pathogenesis and/or drug resistance. Coupled with the chemosensitivities of these samples to FDA-approved oncology drugs, we show how an impartial integrative analysis of these diverse datasets can be used to associate the detected genomic rearrangements with multiple drug sensitivity profiles. Indeed, an insertion in the gene MUSK is shown to be associated with increased sensitivity to the clinically relevant agent Idarubicin, while partial tandem duplication events in the KMT2A gene are related to the efficacy of another frontline treatment, Cytarabine.
摘要：
急性白血病是一个特别有问题的血液癌症集合，and,虽然有点罕见，如果不进行骨髓移植，患者的生存率通常很糟糕。此外，作为患者治疗标准的传统化疗会引起严重的副作用.了解白血病的进化，以确定新的靶标，因此,药物治疗方案是一个重大的医疗需求。基因组重排和其他结构变异（SVs）在多种类型的癌症中一直被认为是致病的。包括白血病.这些SVs可能与癌症的发生有关，programming,克隆进化,和抗药性，和更好地了解个别患者的SV可能有助于指导治疗选择。这里,我们展示了利用光学基因组作图（OGM）来检测白血病患者样本中已知和新颖的SV。重要的是,该技术提供了前所未有的粒度和定量水平，其他当前技术不可用，并允许无偏检测新颖的SV，这可能与疾病的发病机制和/或耐药性有关。再加上这些样本对FDA批准的肿瘤药物的化学敏感性，我们展示了如何对这些不同数据集进行公正的综合分析,将检测到的基因组重排与多种药物敏感性谱相关联.的确,MUSK基因的插入与临床相关药物伊达比星的敏感性增加有关，虽然KMT2A基因的部分串联重复事件与另一种一线治疗的疗效有关，阿糖胞苷.
