Radtke Ina, Mullighan Charles G, Ishii Masami, Su Xiaoping, Cheng Jinjun, Ma Jing, Ganti Ramapriya, Cai Zhongling, Goorha Salil, Pounds Stanley B, Cao Xueyuan, Obert Caroline, Armstrong Jianling, Zhang Jinghui, Song Guangchun, Ribeiro Raul C, Rubnitz Jeffrey E, Raimondi Susana C, Shurtleff Sheila A, Downing James R
Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12944-9. doi: 10.1073/pnas.0903142106. Epub 2009 Jul 27.
Pediatric de novo acute myeloid leukemia (AML) is an aggressive malignancy with current therapy resulting in cure rates of only 60%. To better understand the cause of the marked heterogeneity in therapeutic response and to identify new prognostic markers and therapeutic targets a comprehensive list of the genetic mutations that underlie the pathogenesis of AML is needed. To approach this goal, we examined diagnostic leukemic samples from a cohort of 111 children with de novo AML using single-nucleotide-polymorphism microarrays and candidate gene resequencing. Our data demonstrate that, in contrast to pediatric acute lymphoblastic leukemia (ALL), de novo AML is characterized by a very low burden of genomic alterations, with a mean of only 2.38 somatic copy-number alterations per leukemia, and less than 1 nonsynonymous point mutation per leukemia in the 25 genes analyzed. Even more surprising was the observation that 34% of the leukemias lacked any identifiable copy-number alterations, and 28% of the leukemias with recurrent translocations lacked any identifiable sequence or numerical abnormalities. The only exception to the presence of few mutations was acute megakaryocytic leukemias, with the majority of these leukemias being characterized by a high number of copy-number alterations but rare point mutations. Despite the low overall number of lesions across the patient cohort, novel recurring regions of genetic alteration were identified that harbor known, and potential new cancer genes. These data reflect a remarkably low burden of genomic alterations within pediatric de novo AML, which is in stark contrast to most other human malignancies.
儿童原发性急性髓系白血病（AML）是一种侵袭性恶性肿瘤，目前的治疗方法治愈率仅为60%。为了更好地理解治疗反应中显著异质性的原因，并识别新的预后标志物和治疗靶点，需要一份构成AML发病机制基础的基因突变综合清单。为了实现这一目标，我们使用单核苷酸多态性微阵列和候选基因重测序技术，对111名患有原发性AML的儿童队列中的诊断性白血病样本进行了检测。我们的数据表明，与儿童急性淋巴细胞白血病（ALL）不同，原发性AML的特点是基因组改变负担非常低，每个白血病平均只有2.38个体细胞拷贝数改变，在分析的25个基因中，每个白血病的非同义点突变少于1个。更令人惊讶的是，观察到34%的白血病没有任何可识别的拷贝数改变，28%的复发性易位白血病没有任何可识别的序列或数量异常。唯一突变数量较多的例外是急性巨核细胞白血病，这些白血病中的大多数特点是拷贝数改变数量多但点突变罕见。尽管整个患者队列中的病变总数较少，但仍识别出了新的反复出现的基因改变区域，这些区域包含已知的和潜在的新癌症基因。这些数据反映出儿童原发性AML中基因组改变的负担非常低，这与大多数其他人类恶性肿瘤形成了鲜明对比。
