Russell Lisa J, Jones Lisa, Enshaei Amir, Tonin Stefano, Ryan Sarra L, Eswaran Jeyanthy, Nakjang Sirintra, Papaemmanuil Elli, Tubio Jose M C, Fielding Adele K, Vora Ajay, Campbell Peter J, Moorman Anthony V, Harrison Christine J
Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
Bioinformatics Support Unit, Newcastle University, Newcastle-upon-Tyne, UK.
Genes Chromosomes Cancer. 2017 May;56(5):363-372. doi: 10.1002/gcc.22439. Epub 2017 Jan 18.
Deregulated expression of the type I cytokine receptor, CRLF2, is observed in 5-15% of precursor B-cell acute lymphoblastic leukaemia (B-ALL). We aimed to determine the clinical and genetic landscape of those with IGH-CRLF2 or P2RY8-CRLF2 (CRLF2-r) using multiple genomic approaches. Clinical and demographic features of CRLF2-r patients were characteristic of B-ALL. Patients with IGH-CRLF2 were older (14 y vs. 4 y, P < .001), while the incidence of CRLF2-r among Down syndrome patients was high (50/161, 31%). CRLF2-r co-occurred with primary chromosomal rearrangements but the majority (111/161, 69%) had B-other ALL. Copy number alteration (CNA) profiles were similar to B-other ALL, although CRLF2-r patients harbored higher frequencies of IKZF1 (60/138, 43% vs. 77/1351, 24%) and BTG1 deletions (20/138, 15% vs. 3/1351, 1%). There were significant differences in CNA profiles between IGH-CRLF2 and P2RY8-CRLF2 patients: IKZF1 (25/35, 71% vs. 36/108, 33%, P < .001), BTG1 (11/35, 31% vs. 10/108, 9%, P =.004), and ADD3 deletions (9/19, 47% vs. 5/38, 13%, P =.008). A novel gene fusion, USP9X-DDX3X, was discovered in 10/54 (19%) of patients. Pathway analysis of the mutational profile revealed novel involvement for focal adhesion. Although the functional relevance of many of these abnormalities are unknown, they likely activate additional pathways, which may represent novel therapeutic targets.
在5%至15%的前体B细胞急性淋巴细胞白血病（B-ALL）中观察到I型细胞因子受体CRLF2的表达失调。我们旨在使用多种基因组方法确定那些具有IGH-CRLF2或P2RY8-CRLF2（CRLF2-r）的患者的临床和遗传特征。CRLF2-r患者的临床和人口统计学特征具有B-ALL的特点。IGH-CRLF2患者年龄较大（14岁对4岁，P <.001），而唐氏综合征患者中CRLF2-r的发生率较高（50/161，31%）。CRLF2-r与原发性染色体重排同时出现，但大多数（111/161，69%）为B-其他ALL。拷贝数改变（CNA）谱与B-其他ALL相似，尽管CRLF2-r患者中IKZF1缺失频率更高（60/138，43%对77/1351，24%）和BTG1缺失频率更高（20/138，15%对3/1351，1%）。IGH-CRLF2和P2RY8-CRLF2患者之间的CNA谱存在显著差异：IKZF1（25/35，71%对36/108，33%，P <.001）、BTG1（11/35，31%对10/108，9%，P =.004）和ADD3缺失（9/19，47%对5/38，13%，P =.008）。在10/54（19%）的患者中发现了一种新的基因融合USP9X-DDX3X。对突变谱的通路分析揭示了粘着斑的新参与。尽管这些异常中的许多的功能相关性尚不清楚，但它们可能激活其他通路，这可能代表新的治疗靶点。
