NOTCH1 activation clinically antagonizes the unfavorable effect of PTEN inactivation in BFM-treated children with precursor T-cell acute lymphoblastic leukemia
NOTCH1 activation clinically antagonizes the unfavorable effect of PTEN inactivation in BFM-treated children with precursor T-cell acute lymphoblastic leukemia
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DOI：
10.3324/haematol.2012.073585
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发表时间：
2013-06-01
期刊：
影响因子：
10.1
通讯作者：
Kulozik, Andreas E.
中科院分区：
文献类型：
--
作者：
Bandapalli, Obul R.;Zimmermann, Martin;Kulozik, Andreas E.
尽管儿童T细胞急性淋巴细胞性白血病的治疗结果有所改善，但大约20%的患者复发，预后很差。PTEN失活和NOTCH1激活是已知的常见白血病事件，但它们对预后的影响仍存在争议。我们分析了301例经ALL-BFM治疗的T细胞急性淋巴细胞白血病患儿中PTEN失活及其与NOTCH1激活的相互作用对疗效和长期预后的影响。我们在301例患者中发现了52例PTEN突变(17.3%)。在单变量分析中，这与诱导化疗的抵抗力增加和长期结果差的趋势显着相关。相比之下，PTEN失活和NOTCH1突变激活的患者表现出对诱导治疗的显著敏感性和良好的长期结果，这与仅有NOTCH1突变的患者相似，但比仅有PTEN突变的患者更有利。值得注意的是，在具有强的松和微小残留病(MRD)反应的中等风险特征的患者亚组中，PTEN突变而不共存NOTCH1突变代表了MRD独立的高度显著的高风险生物标记物。PTEN的突变非常显著地表明T-ALL患者的预后很差，这些患者已经被分层到BFM方案的中等风险组。这种效应在临床上被NOTCH1突变所抵消。虽然这些结果还没有得到明显的分子机制的解释，但它们有助于发展新的分子定义分层算法。此外，这些数据对开发NOTCH1抑制剂治疗T细胞急性淋巴细胞白血病具有意想不到的潜在意义，特别是在PTEN和NOTCH1突变组合的患者中。
Despite improvements in treatment results for pediatric T-cell acute lymphoblastic leukemia, approximately 20% of patients relapse with dismal prognosis. PTEN inactivation and NOTCH1 activation are known frequent leukemogenic events but their effect on outcome is still controversial. We analyzed the effect of PTEN inactivation and its interaction with NOTCH1 activation on treatment response and long-term outcome in 301 ALL-BFM treated children with T-cell acute lymphoblastic leukemia. We identified PTEN mutations in 52 of 301 (17.3%) of patients. In univariate analyses this was significantly associated with increased resistance to induction chemotherapy and a trend towards poor long-term outcome. By contrast, patients with inactivating PTEN and activating NOTCH1 mutations showed marked sensitivity to induction treatment and excellent long-term outcome, which was similar to patients with NOTCH1 mutations only, and more favorable than in patients with PTEN mutations only. Notably, in the subgroup of patients with a prednisone-and minimal residual disease (MRD)-response based medium risk profile, PTEN-mutations without co-existing NOTCH1-mutations represented an MRD-independent highly significant high-risk biomarker. Mutations of PTEN highly significantly indicate a poor prognosis in T-ALL patients who have been stratified to the medium risk group of the BFM-protocol. This effect is clinically neutralized by NOTCH1 mutations. Although these results have not yet been explained by an obvious molecular mechanism, they contribute to the development of new molecularly defined stratification algorithms. Furthermore, these data have unexpected potential implications for the development of NOTCH1 inhibitors in the treatment of T-cell acute lymphoblastic leukemia in general, and in those with a combination of PTEN and NOTCH1 mutations in particular.