Institute of Life Sciences, Jiangsu University, Zhenjiang, China.
Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Cancer Med. 2021 Jun;10(12):3997-4003. doi: 10.1002/cam4.3928. Epub 2021 May 13.
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) can be classified into subtypes according to the genetic aberrations they display. For instance, the translocation t(12;21)(p13;q22), representing the ETV6-RUNX1 fusion gene (ER), is present in a quarter of BCP-ALL cases. However, around 10% of the cases lack classifying chromosomal abnormalities (B-other). In pediatric ER BCP-ALL, rearrangement mediated by RAG (recombination-activating genes) has been proposed as the predominant driver of oncogenic rearrangement. Herein we analyzed almost 1600 pediatric BCP-ALL samples to determine which subtypes express RAG. We demonstrate that RAG1 mRNA levels are especially high in the ETV6-RUNX1 (ER) subtype and in a subset of B-other samples. We also define 31 genes that are co-expressed with RAG1 (RAG1-signature) in the ER subtype, a signature that also identifies this subset of B-other samples. Moreover, this subset also shares leukemia and pro-B gene expression signatures as well as high levels of the ETV6 target genes (BIRC7, WBP1L, CLIC5, ANGPTL2) with the ER subtype, indicating that these B-other cases are the recently identified ER-like subtype. We validated our results in a cohort where ER-like has been defined, which confirmed expression of the RAG1-signature in this recently described subtype. Taken together, our results demonstrate that the RAG1-signature identifies the ER-like subtype. As there are no definitive genetic markers to identify this novel subtype, the RAG1-signature represents a means to screen for this leukemia in children.
B 细胞前体急性淋巴细胞白血病 (BCP-ALL) 可以根据其显示的遗传异常进行分类。例如，t(12;21)(p13;q22) 易位代表 ETV6-RUNX1 融合基因 (ER)，存在于四分之一的 BCP-ALL 病例中。然而，约 10%的病例缺乏分类染色体异常 (B-其他)。在儿科 ER BCP-ALL 中，RAG（重组激活基因）介导的重排被认为是致癌重排的主要驱动因素。在此，我们分析了近 1600 例儿科 BCP-ALL 样本，以确定哪些亚型表达 RAG。我们证明，ETV6-RUNX1 (ER) 亚型和一部分 B-其他样本中 RAG1 mRNA 水平特别高。我们还定义了 31 个与 RAG1 共表达的基因（RAG1 特征）在 ER 亚型中，该特征也可识别该部分 B-其他样本。此外，该亚组还与 ER 亚型共享白血病和前 B 细胞基因表达特征以及 ETV6 靶基因（BIRC7、WBP1L、CLIC5、ANGPTL2）的高水平，表明这些 B-其他病例是最近发现的 ER 样亚型。我们在一个已经定义了 ER 样的队列中验证了我们的结果，该队列证实了该最近描述的亚型中 RAG1 特征的表达。总之，我们的结果表明 RAG1 特征可识别 ER 样亚型。由于没有明确的遗传标记来识别这种新的亚型，因此 RAG1 特征代表了一种在儿童中筛查这种白血病的方法。
