Pediatric Oncology/Hematology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands.
Haematologica. 2013 Jun;98(6):937-44. doi: 10.3324/haematol.2012.067983. Epub 2013 Feb 12.
Acute lymphoblastic leukemia in infants represents an aggressive malignancy associated with a high incidence (approx. 80%) of translocations involving the Mixed Lineage Leukemia (MLL) gene. Attempts to mimic Mixed Lineage Leukemia fusion driven leukemogenesis in mice raised the question whether these fusion proteins require secondary hits. RAS mutations are suggested as candidates. Earlier results on the incidence of RAS mutations in Mixed Lineage Leukemia-rearranged acute lymphoblastic leukemia are inconclusive. Therefore, we studied frequencies and relation with clinical parameters of RAS mutations in a large cohort of infant acute lymphoblastic leukemia patients. Using conventional sequencing analysis, we screened neuroblastoma RAS viral (v-ras) oncogene homolog gene (NRAS), v-Ki-ras Kirsten rat sarcoma viral oncogene homolog gene (KRAS), and v-raf murine sarcoma viral oncogene homolog B1 gene (BRAF) for mutations in a large cohort (n=109) of infant acute lymphoblastic leukemia patients and studied the mutations in relation to several clinical parameters, and in relation to Homeobox gene A9 expression and the presence of ALL1 fused gene 4-Mixed Lineage Leukemia (AF4-MLL). Mutations were detected in approximately 14% of all cases, with a higher frequency of approximately 24% in t(4;11)-positive patients (P=0.04). Furthermore, we identified RAS mutations as an independent predictor (P=0.019) for poor outcome in Mixed Lineage Leukemia-rearranged infant acute lymphoblastic leukemia, with a hazard ratio of 3.194 (95% confidence interval (CI):1.211-8.429). Also, RAS-mutated infants have higher white blood cell counts at diagnosis (P=0.013), and are more resistant to glucocorticoids in vitro (P<0.05). Finally, we demonstrate that RAS mutations, and not the lack of Homeobox gene A9 expression nor the expression of AF4-MLL are associated with poor outcome in t(4;11)-rearranged infants. We conclude that the presence of RAS mutations in Mixed Lineage Leukemia-rearranged infant acute lymphoblastic leukemia is an independent predictor for a poor outcome. Therefore, future risk-stratification based on abnormal RAS-pathway activation and RAS-pathway inhibition could be beneficial in RAS-mutated infant acute lymphoblastic leukemia patients.
婴儿急性淋巴细胞白血病代表一种侵袭性恶性肿瘤,其易发性(约 80%)与涉及混合谱系白血病(MLL)基因的易位有关。试图在小鼠中模拟混合谱系白血病融合驱动的白血病发生,提出了这些融合蛋白是否需要二次打击的问题。RAS 突变被认为是候选者。关于混合谱系白血病重排的急性淋巴细胞白血病中 RAS 突变的发生率的早期结果尚无定论。因此,我们在一大群婴儿急性淋巴细胞白血病患者中研究了 RAS 突变的频率及其与临床参数的关系。使用常规测序分析,我们筛选了神经母细胞瘤 RAS 病毒(v-ras)癌基因同源基因(NRAS)、v-Ki-ras Kirsten 大鼠肉瘤病毒癌基因同源基因(KRAS)和 v-raf 鼠肉瘤病毒癌基因同源 B1 基因(BRAF)在一大群(n=109)婴儿急性淋巴细胞白血病患者中发生突变,并研究了突变与几个临床参数的关系,以及与同源盒基因 A9 表达和 ALL1 融合基因 4-混合谱系白血病(AF4-MLL)的关系。大约 14%的病例中检测到突变,t(4;11)阳性患者的频率约为 24%(P=0.04)。此外,我们发现 RAS 突变是混合谱系白血病重排婴儿急性淋巴细胞白血病不良预后的独立预测因子(P=0.019),风险比为 3.194(95%置信区间(CI):1.211-8.429)。此外,RAS 突变的婴儿在诊断时白细胞计数较高(P=0.013),并且在体外对糖皮质激素的耐药性更高(P<0.05)。最后,我们证明,RAS 突变,而不是缺乏同源盒基因 A9 表达或表达 AF4-MLL,与 t(4;11)重排婴儿的不良预后相关。我们得出结论,在混合谱系白血病重排的婴儿急性淋巴细胞白血病中存在 RAS 突变是不良预后的独立预测因子。因此,基于异常 RAS 通路激活和 RAS 通路抑制的未来风险分层可能对 RAS 突变的婴儿急性淋巴细胞白血病患者有益。