Breit Stephen, Stanulla Martin, Flohr Thomas, Schrappe Martin, Ludwig Wolf-Dieter, Tolle Gabriele, Happich Margit, Muckenthaler Martina U, Kulozik Andreas E
Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, D-69120 Heidelberg, Germany.
Blood. 2006 Aug 15;108(4):1151-7. doi: 10.1182/blood-2005-12-4956. Epub 2006 Apr 13.
Activating mutations of the transmembrane receptor NOTCH1 are common in precursor T-cell lymphoblastic leukemia (T-ALL). We systematically analyzed the impact of activating NOTCH1 mutations on early treatment response and long-term outcome in 157 patients with T-ALL of the pediatric ALL-Berlin-Frankfurt-Munster (BFM) 2000 study. We confirm previous results that NOTCH1 mutations occur in more than 50% of T-ALL in children. In 82 patients (82/157; 52.2%), activating NOTCH1 mutations were identified either in the heterodimerization (55/82; 67.1%), in the PEST (13/82; 15.9%), or in both domains (14/82; 17.0%). The presence of NOTCH1 mutations was significantly correlated with a good prednisone response and favorable minimal residual disease (MRD) kinetics, which was independent from sex, age, white blood cell count, and T-cell immunophenotype at the time of diagnosis. Furthermore, activating NOTCH1 mutations specified a large subgroup of patients with an excellent prognosis. These findings indicate that in the context of the ALL-BFM 2000 treatment strategy, NOTCH1 mutations predict a more rapid early treatment response and a favorable long-term outcome in children with T-ALL.
跨膜受体NOTCH1的激活突变在T细胞前体淋巴细胞白血病（T-ALL）中很常见。我们系统分析了激活型NOTCH1突变对157例儿童ALL-柏林-法兰克福-明斯特（BFM）2000研究中T-ALL患者早期治疗反应和长期预后的影响。我们证实了之前的结果，即超过50%的儿童T-ALL中存在NOTCH1突变。在82例患者（82/157；52.2%）中，激活型NOTCH1突变被确定存在于异二聚化结构域（55/82；67.1%）、PEST结构域（13/82；15.9%）或两个结构域中均有（14/82；17.0%）。NOTCH1突变的存在与泼尼松反应良好及微小残留病（MRD）动力学良好显著相关，这与诊断时的性别、年龄、白细胞计数和T细胞免疫表型无关。此外，激活型NOTCH1突变明确了一个预后极佳的大患者亚组。这些发现表明，在ALL-BFM 2000治疗策略背景下，NOTCH1突变预示着儿童T-ALL患者早期治疗反应更快且长期预后良好。
