The Biology and Targeting of FLT3 in Pediatric Leukemia.
The Biology and Targeting of FLT3 in Pediatric Leukemia.
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DOI：
10.3389/fonc.2014.00263
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发表时间：
2014
影响因子：
4.7
通讯作者：
Brown P
中科院分区：
文献类型：
--
作者：
Annesley CE;Brown P
尽管在过去的几十年里，儿科白血病的治疗结果有了显著的改善，但急性髓性白血病（AML）和急性淋巴细胞白血病（ALL）的高危人群以及复发性白血病的预后仍然很差。对高危人群加强化疗方案可以提高成功率，但代价是发病率和长期不良反应显著增加。随着伊马替尼在费城染色体阳性白血病和全反式维甲酸在急性早幼粒细胞白血病中的成功，近年来寻找其他分子靶向疗法的努力引起了人们的极大兴奋。儿科急性白血病的另一个可能的靶点是FMS样酪氨酸激酶3（FLT3）。FLT3畸变是AML中最常见的转化事件之一，在高危儿童AML和某些高危儿童ALL组中具有显著的临床意义。因此，成功靶向FLT3具有改善这些患者亚群结局的巨大潜力。本文就FLT3受体的分子功能、信号转导及其在白血病中的致病作用作一综述。我们回顾了靶向FLT3的发现，讨论了目前儿科白血病中可用的FLT3抑制剂和迄今为止的临床试验结果，最后，考虑了FLT3抑制剂治疗的未来前景和挑战。
Despite remarkable improvement in treatment outcomes in pediatric leukemia over the past several decades, the prognosis for high-risk groups of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), as well as for relapsed leukemia, remains poor. Intensification of chemotherapy regimens for those at highest risk has improved success rates, but at the cost of significantly increased morbidity and long-term adverse effects. With the success of imatinib in Philadelphia-chromosome-positive leukemia and all-trans retinoic acid in acute promyelocytic leukemia, the quest to find additional molecularly targeted therapies has generated much excitement over recent years. Another such possible target in pediatric acute leukemia is FMS-like tyrosine kinase 3 (FLT3). FLT3 aberrations are among the most frequently identified transforming events in AML, and have significant clinical implications in both high-risk pediatric AML and in certain high-risk groups of pediatric ALL. Therefore, the successful targeting of FLT3 has tremendous potential to improve outcomes in these subsets of patients. This article will give an overview of the molecular function and signaling of the FLT3 receptor, as well as its pathogenic role in leukemia. We review the discovery of targeting FLT3, discuss currently available FLT3 inhibitors in pediatric leukemia and results of clinical trials to date, and finally, consider the future promise and challenges of FLT3 inhibitor therapy.