Molecular characterization of acute lymphoblastic leukemia with high CRLF2 gene expression in childhood
Molecular characterization of acute lymphoblastic leukemia with high CRLF2 gene expression in childhood
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DOI：
10.1002/pbc.26539
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发表时间：
2017-10-01
影响因子：
3.2
通讯作者：
Cario, Gunnar
中科院分区：
文献类型：
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作者：
Schmaeh, Juliane;Fedders, Birthe;Cario, Gunnar
研究背景CRLF 2基因在前体B细胞急性淋巴细胞白血病（precursor B-cell acute lymphoblastic leukemia，pB-ALL）中高表达，可由不同的基因畸变引起。根据ALL-Berlin-Frankfurt-Munster（BFM）方案治疗的儿童中，最常见的改变P2 RY 8/CRLF 2融合的存在与高复发率相关，但对此了解甚少。此外，其他改变的频率尚未进行系统分析。程序CRLF 2 mRNA表达和导致CRLF 2高表达的潜在遗传畸变在1，105例根据意大利儿科肿瘤协会（AIEOP）-BFM ALL 2009方案治疗的患者中进行了前瞻性评估。此外，我们确定了所有CRLF 2高表达pB-ALL的情况下，以及JAK 2和CRLF 2 mutation.ResultsA CRLF 2高表达的B细胞分化基因的拷贝数改变检测到26/178（15%）的T细胞急性淋巴细胞白血病（T-ALL）的情况下，其中21人（81%）已分层为高风险患者的治疗反应。在pB-ALL中，91/927（10%）例病例中确定了CRLF 2高表达;其中44/91（48%）例病例中存在P2 RY 8/CRLF 2重排，18/91（20%）例病例中存在CRLF 2的额外拷贝，值得注意的是，16/91（18%）例病例中检测到IGH/CRLF 2易位。值得注意的是，16例IGH/CRLF 2易位患者中有7例（44%）已经复发。P2 RY 8/CRLF 2和IGH/CRLF 2阳性患者中IKZF 1和PAX 5等B细胞分化基因缺失率分别为70%和94%。结论在CRLF 2高表达的背景下，这种高频率的遗传变异可能是P2 RY 8/CRLF 2和IGH/CRLF 2阳性ALL复发的高风险因素。
BackgroundA high-level expression of the CRLF2 gene is frequent in precursor B-cell acute lymphoblastic leukemia (pB-ALL) and can be caused by different genetic aberrations. The presence of the most frequent alteration, the P2RY8/CRLF2 fusion, was shown to be associated with a high relapse incidence in children treated according to ALL-Berlin-Frankfurt-Munster (BFM) protocols, which is poorly understood. Moreover, the frequency of other alterations has not been systematically analyzed yet.ProcedureCRLF2 mRNA expression and potential genetic aberrations causing a CRLF2 high expression were prospectively assessed in 1,105 patients treated according to the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP)-BFM ALL 2009 protocol. Additionally, we determined copy number alterations in selected B-cell differentiation genes for all CRLF2 high-expressing pB-ALL cases, as well as JAK2 and CRLF2 mutations.ResultsA CRLF2 high expression was detected in 26/178 (15%) T-cell acute lymphoblastic leukemia (T-ALL) cases, 21 of them (81%) had been stratified as high-risk patients by treatment response. In pB-ALL, a CRLF2 high expression was determined in 91/927 (10%) cases; the P2RY8/CRLF2 rearrangement in 44/91 (48%) of them, supernumerary copies of CRLF2 in 18/91 (20%), and, notably, the IGH/CRLF2 translocation was detected in 16/91 (18%). Remarkably, 7 of 16 (44%) patients with IGH/CRLF2 translocation had already relapsed. P2RY8/CRLF2- and IGH/CRLF2-positive samples (70 and 94%, respectively) were characterized by a high frequency of additional deletions in B-cell differentiation genes such as IKZF1 or PAX5.ConclusionOur data suggest that this high frequency of genetic aberrations in the context of a high CRLF2 expression could contribute to the high risk of relapse in P2RY8/CRLF2- and IGH/CRLF2-positive ALL.