Department of Experimental Hematology, Cancer Research Centre Groningen (CRCG), University Medical Centre Groningen, University of Groningen, Hanzeplein 1, DA13, 9700 RB Groningen, the Netherlands.
Institute for Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, B15 2TT Birmingham, UK.
Cancer Cell. 2018 Oct 8;34(4):674-689.e8. doi: 10.1016/j.ccell.2018.08.014. Epub 2018 Sep 20.
Intra-tumor heterogeneity caused by clonal evolution is a major problem in cancer treatment. To address this problem, we performed label-free quantitative proteomics on primary acute myeloid leukemia (AML) samples. We identified 50 leukemia-enriched plasma membrane proteins enabling the prospective isolation of genetically distinct subclones from individual AML patients. Subclones differed in their regulatory phenotype, drug sensitivity, growth, and engraftment behavior, as determined by RNA sequencing, DNase I hypersensitive site mapping, transcription factor occupancy analysis, in vitro culture, and xenograft transplantation. Finally, we show that these markers can be used to identify and longitudinally track distinct leukemic clones in patients in routine diagnostics. Our study describes a strategy for a major improvement in stratifying cancer diagnosis and treatment.
肿瘤内的克隆进化引起的异质性是癌症治疗的一个主要问题。为了解决这个问题，我们对原发性急性髓系白血病 (AML) 样本进行了无标记定量蛋白质组学分析。我们鉴定了 50 种富含白血病的质膜蛋白，这些蛋白能够从单个 AML 患者中前瞻性地分离出具有遗传差异的亚克隆。通过 RNA 测序、DNase I 超敏位点作图、转录因子占据分析、体外培养和异种移植，确定了亚克隆在调控表型、药物敏感性、生长和植入行为上的差异。最后，我们证明这些标志物可用于在常规诊断中识别和纵向跟踪患者中不同的白血病克隆。我们的研究描述了一种用于改善癌症诊断和治疗分层的策略。
