The prognostic significance of cytokine receptor-like factor 2 expression and JAK2 mutation in pediatric B-cell acute lymphoblastic leukemia: A prospective cohort study
M. Abd El Monem, R. El Ashry, M. Bassiouny, S. Aref, S. Abd El Mabood
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引用次数: 0
Abstract
Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Philadelphia (Ph)-like B-cell acute lymphoblastic leukemia (B-ALL) is defined by a gene expression profile similar to Phpositive B-ALL and shows a large number of genetic alterations in the cytokine receptor and kinasesignaling pathway genes that contribute to its aggressive phenotype and frequent disease recurrence – the main cause of death in affected children. Here, we aimed to correlate CRLF2 expression and JAK2 mutations in B-ALL patients with other prognostic factors and the patients’ outcomes as well as to evaluate their prognostic significance. The study was approved by the local institutional review board and written consents were obtained from a parent of each child before their enrolment. We included 54 newly diagnosed B-ALL pediatric patients (median age: 9.0 (2.0–18.0)) who were stratified either into a standard-risk (SR) or high-risk (HR) group and treated according to the modified BerlinFrankfurt-Münster 90 protocol (ALL-BFM 90). Fresh bone marrow samples were used to determine CRLF2 expression as well as to search for the JAK2 V617F mutation. Normal CRLF2 expression was reported in the SR patients much more often than in the HR group, while its overexpression was more common in the HR patients than in the SR ones (22 vs 6 and 18 vs 8, respectively, p < 0.001). CRLF2 was also more often overexpressed in the MRD-positive cases than in the negative ones (17 vs 9, p < 0.001), while normal CRLF2 expression was more common in the MRD-negative patients compared to the MRD-positive ones (24 vs 4, p < 0.001) which supports the unfavorable prognostic value of CRLF2 in relation to MRD positivity at the end of the induction treatment. JAK2 mutation was detected only in 2 patients belonging to the CRLF2 overexpression group which made the assessment of the prognostic significance of this mutation impossible. Notably, none of the patients with normal CRLF2 expression ended up relapsing while 4 patients with overexpressed CRLF2 developed a relapse (p = 0.031). The study subjects were followed up for up to 24 months, and we did not find CRLF2 overexpression to negatively influence overall survival, however, it did have an adverse effect on relapse-free survival. In summary, CRLF2 overexpression was found to be an unfavorable prognostic factor in childhood ALL as it was expressed more in high-risk patients and in those with poor treatment response. The analysis of CRLF2 expression in B-ALL pediatric patients may help in risk stratification and can potentially offer new treatment options based on novel CRLF2 inhibitors.
急性淋巴细胞白血病(ALL)是儿童最常见的恶性肿瘤。费城(Ph)样b细胞急性淋巴细胞白血病(B-ALL)是由与Phpositive B-ALL相似的基因表达谱定义的,并且在细胞因子受体和激酶信号通路基因中显示大量遗传改变,这些基因导致其侵袭性表型和频繁的疾病复发,这是受影响儿童死亡的主要原因。在这里,我们旨在将B-ALL患者的CRLF2表达和JAK2突变与其他预后因素和患者预后联系起来,并评估其预后意义。这项研究得到了当地机构审查委员会的批准,并在每个孩子参加研究前获得了他们父母的书面同意。我们纳入了54例新诊断的B-ALL儿童患者(中位年龄:9.0(2.0-18.0)),他们被分为标准风险组(SR)或高风险组(HR),并根据修改的柏林法兰克福- nster 90方案(ALL-BFM 90)进行治疗。新鲜骨髓样本用于检测CRLF2表达以及寻找JAK2 V617F突变。CRLF2在SR患者中正常表达的频率远高于HR组,而其过表达在HR患者中比SR组更常见(分别为22比6和18比8,p < 0.001)。CRLF2在MRD阳性患者中也比在MRD阴性患者中更常过表达(17 vs 9, p < 0.001),而在MRD阴性患者中,CRLF2的正常表达比MRD阳性患者更常见(24 vs 4, p < 0.001),这支持了诱导治疗结束时CRLF2对MRD阳性患者的不利预后价值。JAK2突变仅在2例属于CRLF2过表达组的患者中检测到,这使得无法评估该突变的预后意义。值得注意的是,CRLF2正常表达的患者无复发,而CRLF2过表达的患者有4例复发(p = 0.031)。对研究对象进行了长达24个月的随访,我们没有发现CRLF2过表达对总体生存产生负面影响,然而,它确实对无复发生存产生不利影响。总之,CRLF2过表达在儿童ALL中是一个不利的预后因素,因为它在高危患者和治疗反应较差的患者中表达更多。分析B-ALL儿童患者的CRLF2表达可能有助于风险分层,并可能提供基于新型CRLF2抑制剂的新治疗方案。