Mouse Genomics Team, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
Nat Genet. 2011 May;43(5):470-5. doi: 10.1038/ng.796. Epub 2011 Mar 27.
Acute myeloid leukemia (AML) is a molecularly diverse malignancy with a poor prognosis whose largest subgroup is characterized by somatic mutations in NPM1, which encodes nucleophosmin. These mutations, termed NPM1c, result in cytoplasmic dislocation of nucleophosmin and are associated with distinctive transcriptional signatures, yet their role in leukemogenesis remains obscure. Here we report that activation of a humanized Npm1c knock-in allele in mouse hemopoietic stem cells causes Hox gene overexpression, enhanced self renewal and expanded myelopoiesis. One third of mice developed delayed-onset AML, suggesting a requirement for cooperating mutations. We identified such mutations using a Sleeping Beauty transposon, which caused rapid-onset AML in 80% of mice with Npm1c, associated with mutually exclusive integrations in Csf2, Flt3 or Rasgrp1 in 55 of 70 leukemias. We also identified recurrent integrations in known and newly discovered leukemia genes including Nf1, Bach2, Dleu2 and Nup98. Our results provide new pathogenetic insights and identify possible therapeutic targets in NPM1c+ AML.
急性髓系白血病 (AML) 是一种分子多样性恶性肿瘤，预后不良，其最大亚组的特征是存在 NPM1 体细胞突变，该基因编码核仁磷酸蛋白。这些突变被称为 NPM1c，导致核仁磷酸蛋白的细胞质易位，并与独特的转录特征相关，但它们在白血病发生中的作用仍不清楚。在这里，我们报告说，在小鼠造血干细胞中激活人源化 Npm1c 敲入等位基因会导致 Hox 基因过表达、自我更新增强和髓系扩增。三分之一的小鼠发生迟发性 AML，提示需要协同突变。我们使用 Sleeping Beauty 转座子来识别这些突变，该突变导致 80%携带 Npm1c 的小鼠发生快速发作 AML，与 70 例白血病中的 55 例中 CSF2、Flt3 或 Rasgrp1 中相互排斥的整合相关。我们还在已知和新发现的白血病基因中发现了反复的整合，包括 Nf1、Bach2、Dleu2 和 Nup98。我们的研究结果提供了新的发病机制见解，并确定了 NPM1c+AML 中的可能治疗靶点。
