Terminal myeloid differentiation in vivo is induced by FLT3 inhibition in FLT3/ITDAML
Terminal myeloid differentiation in vivo is induced by FLT3 inhibition in FLT3/ITDAML
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DOI：
10.1182/blood-2012-01-402545
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发表时间：
2012-11-15
期刊：
影响因子：
20.3
通讯作者：
Levis, Mark
中科院分区：
文献类型：
--
作者：
Sexauer, Amy;Perl, Alexander;Levis, Mark
癌症的标志是肿瘤细胞内分化的破坏。FLT 3激酶的内部串联重复突变（FLT 3/ITD）通常发生在急性髓性白血病（AML）中，并与生存率低相关，导致开发FLT 3激酶抑制剂的努力。然而，FLT 3抑制剂迄今为止取得的成功有限，仅诱导外周原始细胞的清除，BM反应最小。Quizartinib是一种新型的强效和选择性FLT 3抑制剂，目前正在临床试验中进行研究。在接受quizartinib治疗的14例核型正常的FLT 3/ITD AML患者中，我们观察到BM原始细胞的终末髓样分化与临床分化综合征相关。原始细胞未能分化的单个患者具有预先存在的C/EBP α突变，另一名患者在疾病进展时发生C/EBP α突变，表明对FLT 3抑制的耐药机制。在体外，在与人BM基质共培养的原代母细胞中，quizartinib抑制FLT 3诱导细胞周期停滞和分化，而不是细胞凋亡。本研究是第一次描述的终末分化的癌细胞在患者治疗酪氨酸激酶抑制剂。这些数据突出了分化阻滞在AML病理发生中的重要性。（血。2012; 120（20）：4205-4214）
A hallmark of cancer is the disruption of differentiation within tumor cells. Internal tandem duplication mutations of the FLT3 kinase (FLT3/ITD) occur commonly in acute myeloid leukemia (AML) and are associated with poor survival, leading to efforts to develop FLT3 kinase inhibitors. However, FLT3 inhibitors have thus far met with limited success, inducing only a clearance of peripheral blasts with minimal BM responses. Quizartinib is a novel potent and selective FLT3 inhibitor currently being studied in clinical trials. In 13 of 14 FLT3/ITD AML patients with normal karyotype treated with quizartinib, we observed terminal myeloid differentiation of BM blasts in association with a clinical differentiation syndrome. The single patient whose blasts failed to differentiate had a preexisting C/EBP alpha mutation and another developed a C/EBP alpha mutation at disease progression, suggesting a mechanism of resistance to FLT3 inhibition. In vitro, in primary blasts cocultured with human BM stroma, FLT3 inhibition with quizartinib induced cell-cycle arrest and differentiation rather than apoptosis. The present study is the first description of terminal differentiation of cancer cells in patients treated with a tyrosine kinase inhibitor. These data highlight the importance of the differentiation block in the patho-genesis of AML. (Blood. 2012; 120(20): 4205-4214)