RUNX1 基因突变与细胞遗传学正常的急性髓系白血病不良预后相关，并导致淋巴样基因的上调。
RUNX1 mutations in cytogenetically normal acute myeloid leukemia are associated with a poor prognosis and up-regulation of lymphoid genes.
机构信息
Department of Internal Medicine 3, Ludwig-Maximilians-Universität (LMU) Munich, Munich, Germany.
出版信息
Haematologica. 2012 Dec;97(12):1909-15. doi: 10.3324/haematol.2012.064667. Epub 2012 Jun 11.
BACKGROUND
The RUNX1 (AML1) gene is a frequent mutational target in myelodysplastic syndromes and acute myeloid leukemia. Previous studies suggested that RUNX1 mutations may have pathological and prognostic implications.
DESIGN AND METHODS
We screened 93 patients with cytogenetically normal acute myeloid leukemia for RUNX1 mutations by capillary sequencing of genomic DNA. Mutation status was then correlated with clinical data and gene expression profiles.
RESULTS
We found that 15 out of 93 (16.1%) patients with cytogenetically normal acute myeloid leukemia had RUNX1 mutations. Seventy-three patients were enrolled in the AMLCG-99 trial and carried ten RUNX1 mutations (13.7%). Among these 73 patients RUNX1 mutations were significantly associated with older age, male sex, absence of NPM1 mutations and presence of MLL-partial tandem duplications. Moreover, RUNX1-mutated patients had a lower complete remission rate (30% versus 73% P=0.01), lower relapse-free survival rate (3-year relapse-free survival 0% versus 30.4%; P=0.002) and lower overall survival rate (3-year overall survival 0% versus 34.4%; P<0.001) than patients with wild-type RUNX1. RUNX1 mutations remained associated with shorter overall survival in a multivariate model including age and the European Leukemia Net acute myeloid leukemia genetic classification as covariates. Patients with RUNX1 mutations showed a unique gene expression pattern with differential expression of 85 genes. The most prominently up-regulated genes in patients with RUNX1-mutated cytogenetically normal acute myeloid leukemia include lymphoid regulators such as HOP homeobox (HOPX), deoxynucleotidyltransferase (DNTT, terminal) and B-cell linker (BLNK), indicating lineage infidelity.
CONCLUSIONS
Our findings firmly establish that RUNX1 mutations are a marker of poor prognosis and provide insights into the pathogenesis of RUNX1 mutation-positive acute myeloid leukemia.
背景
RUNX1（AML1）基因是骨髓增生异常综合征和急性髓系白血病的常见突变靶点。先前的研究表明，RUNX1 突变可能具有病理和预后意义。
设计和方法
我们通过基因组 DNA 的毛细管测序筛选了 93 例核型正常的急性髓系白血病患者的 RUNX1 突变。然后将突变状态与临床数据和基因表达谱相关联。
结果
我们发现 93 例核型正常的急性髓系白血病患者中有 15 例（16.1%）存在 RUNX1 突变。73 例患者纳入 AMLCG-99 试验，携带 10 种 RUNX1 突变（13.7%）。在这 73 例患者中，RUNX1 突变与年龄较大、男性、无 NPM1 突变和存在 MLL 部分串联重复显著相关。此外，RUNX1 突变患者的完全缓解率较低（30%对 73%，P=0.01），无复发生存率较低（3 年无复发生存率 0%对 30.4%，P=0.002），总生存率较低（3 年总生存率 0%对 34.4%，P<0.001）。在包括年龄和欧洲白血病网急性髓系白血病遗传分类作为协变量的多变量模型中，RUNX1 突变与较短的总生存期相关。RUNX1 突变患者表现出独特的基因表达模式，85 个基因的表达存在差异。RUNX1 突变的核型正常急性髓系白血病患者中最显著上调的基因包括淋巴样调节因子，如 HOP 同源盒（HOPX）、脱氧核苷酸转移酶（DNTT，末端）和 B 细胞接头（BLNK），表明谱系失实。
结论
我们的发现牢固确立了 RUNX1 突变是预后不良的标志物，并提供了对 RUNX1 突变阳性急性髓系白血病发病机制的深入了解。
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