Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia
Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia
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DOI：
10.1038/sj.leu.2403870
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发表时间：
2005-09-01
期刊：
影响因子：
11.4
通讯作者：
Heinrich, MC
中科院分区：
文献类型：
--
作者：
Goemans, BF;Zwaan, CM;Heinrich, MC
RAS和受体酪氨酸激酶（如KIT和FLT 3）的激活突变被假设与嵌合转录因子在急性髓细胞白血病（AML）的发病机制中相互作用。为了验证这一假设，我们对150例儿童AML样本进行了KIT（外显子8、17）、NRAS和KRAS（外显子1、2）以及FLT 3/ITD突变的基因分型。这是迄今为止报告的筛查所有四种突变的最大的儿科AML患者队列。在AML患儿中，40%的患儿存在KIT（11.3%）、RAS（18%）或FLT 3/ITD（11.1%）突变，70%的核心结合因子（CBF）白血病病例与KIT或RAS突变相关。RAS或FLT 3/ITD突变常与正常核型相关。FLT 3/ITD突变患者的临床结局显著较差。然而，KIT或RAS突变的存在并不显著影响临床结果。我们证明，KIT外显子8突变导致组成型配体非依赖性激酶激活，可被临床相关浓度的伊马替尼抑制。我们的研究结果表明，异常的信号转导途径是常见的儿童AML。未来的临床研究需要确定是否选择性靶向这些异常将改善治疗结果。
Activating mutations in RAS and receptor tyrosine kinases such as KIT and FLT3 are hypothesized to cooperate with chimeric transcription factors in the pathogenesis of acute myeloid leukemia (AML). To test this hypothesis, we genotyped 150 pediatric AML samples for mutations in KIT (exons 8, 17), NRAS and KRAS ( exons 1, 2) and FLT3/ITD. This is the largest cohort of pediatric AML patients reported thus far screened for all four mutations. Of the children with AML, 40% had a mutation in KIT (11.3%), RAS (18%) or FLT3/ITD (11.1%), and 70% of cases of core-binding factor (CBF) leukemia were associated with a mutation of KIT or RAS. Mutations in RAS or FLT3/ITD were frequently found in association with a normal karyotype. Patients with a FLT3/ITD mutation had a significantly worse clinical outcome. However, the presence of a KIT or RAS mutation did not significantly influence clinical outcome. We demonstrate that KIT exon 8 mutations result in constitutive ligand-independent kinase activation that can be inhibited by clinically relevant concentrations of imatinib. Our results demonstrate that abnormalities of signal transduction pathways are frequent in pediatric AML. Future clinical studies are needed to determine whether selective targeting of these abnormalities will improve treatment results.