Spectrum of Mutations in Myeloid Neoplasms

Patients with myeloid malignancies bearing high-risk cytogenetic abnormalities lack effective therapies and have a poor overall survival. -7/del(7q) is identified in half of high-risk myeloid neoplasms. We recently identified CUX1 to be a haploinsufficient myeloid tumor suppressor gene located within the commonly deleted segment of 7q22. Here we identify the spectrum of somatic mutations that co-occur with loss of CUX1 and chromosome 7 in patients with de novo acute myeloid leukemia (AML) or a therapy-related myeloid neoplasm. -7/del(7q) leukemias have a distinct mutational profile characterized by low frequencies of alterations in major leukemogenic pathways, including genes encoding transcription factors, cohesin, and DNA-methylation-related proteins. In contrast, RAS pathway activating mutations occurred in 40% of -7/del(7q) samples, a significantly higher frequency than other AMLs and higher than previously reported. As targeted therapeutics advance, our data provide guidance for which pathways are most relevant in the treatment of adverse-risk myeloid leukemia. ]]>携带高危细胞遗传学异常的髓系恶性肿瘤患者缺乏有效治疗方案，且总生存期较差。-7/del(7q)在半数高危髓系肿瘤中被检出。我们先前已明确，定位于7q22常见缺失区段的CUX1是一种单倍体不足型髓系肿瘤抑制基因。本研究明确了初发性急性髓系白血病（acute myeloid leukemia, AML）或治疗相关髓系肿瘤患者中，与CUX1缺失及7号染色体缺失共存的体细胞突变谱。-7/del(7q)白血病具有独特的突变特征：主要致白血病通路的变异检出频率较低，这些通路涵盖编码转录因子、黏连蛋白（cohesin）及DNA甲基化相关蛋白的编码基因。与之相对，RAS通路激活突变在40%的-7/del(7q)样本中被检出，其频率显著高于其他AML亚型，也高于既往报道的结果。随着靶向治疗技术的发展，本研究数据可为高危髓系白血病的针对性治疗通路选择提供科学指导。