The response of childhood acute lymphoblastic leukemia (ALL) to dexamethasone predicts the long-term remission outcome. To explore the mechanisms of dexamethasone resistance in B cell ALL (B-ALL), we generated dexamethasone-resistant clones by prolonged treatment with dexamethasone. Using RNA-sequencing and high-throughput screening, we found that dexamethasone-resistant cells are dependent on receptor tyrosine kinases. Further analysis with phosphokinase arrays showed that the type III receptor tyrosine kinase FLT3 is constitutively active in resistant cells. Targeted next-generation and Sanger sequencing identified an internal tandem duplication mutation and a point mutation (R845G) in FLT3 in dexamethasone-resistant cells, which were not present in the corresponding sensitive clones. Finally, we showed that resistant cells displayed sensitivity to second-generation FLT3 inhibitors both in vitro and in vivo. Collectively, our data suggest that long-term dexamethasone treatment selects cells with a distinct genetic background, in this case oncogenic FLT3, and therefore therapies targeting FLT3 might be useful for the treatment of relapsed B-ALL patients.

儿童急性淋巴细胞白血病（ALL）对地塞米松的反应可预测长期缓解的结果。为了探索地塞米松在B细胞ALL（B-ALL）中的抗性机制，我们通过长时间使用地塞米松治疗产生了地塞米松抗性克隆。使用RNA测序和高通量筛选，我们发现地塞米松耐药细胞依赖于受体酪氨酸激酶。磷酸激酶阵列的进一步分析表明，III型受体酪氨酸激酶FLT3在耐药细胞中具有组成型活性。靶向的下一代测序和Sanger测序在地塞米松抗性细胞中的FLT3中鉴定出内部串联重复突变和点突变（R845G），而相应的敏感克隆中没有这种突变。最后，我们发现抗性细胞在体外和体内均表现出对第二代FLT3抑制剂的敏感性。总体而言，我们的数据表明，长期地塞米松治疗会选择具有独特遗传背景的细胞，在这种情况下为致癌的FLT3，因此靶向FLT3的疗法可能对复发的B-ALL患者有用。