RNA-based FLT3-ITD allelic ratio is associated with outcome and ex vivo response to FLT3 inhibitors in pediatric AML
RNA-based FLT3-ITD allelic ratio is associated with outcome and ex vivo response to FLT3 inhibitors in pediatric AML
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DOI：
10.1182/blood-2017-12-819508
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发表时间：
2018-05-31
期刊：
影响因子：
20.3
通讯作者：
Cloos, Jacqueline
中科院分区：
文献类型：
--
作者：
Cucchi, David G. J.;Denys, Barbara;Cloos, Jacqueline
fms样酪氨酸激酶3 （FLT3-internal tandem duplication [ITD]）等位基因比例（AR）和/或ITD长度是否应被考虑在儿童急性髓性白血病（AML）的风险分层中，以及是否应在RNA或DNA上进行测量，目前存在争议。此外，ITD状态可能与选择符合FLT3抑制剂条件的患者相关。在这里，我们纳入了172例儿科AML患者，其中36例（21%）携带FLT3-ITD（通过RNA和DNA检测）。尽管参数AR(spearman) = 0.62（95%可信区间，0.22-0.87）和ITDlength(spearman) = 0.98（95%可信区间，0.90-1.00）之间存在良好的相关性，但基于RNA测量的AR >= 0.5和长度>= 48碱基对（bps）与总生存率显著相关（AR: P-logrank = 0.008; ITDlength: P-logrank = 0.011）。在大的ITDs （DNA上的bbb156bp）中，DNA和RNA之间存在显著的90 bp的差异，包括在RNA中剪接的内含子14。体外暴露于FLT3抑制剂（n = 30），特别是FLT3特异性抑制剂gilteritinib，表明与itd - ar低和ITD2患者样本相比，FLT3- itd - ar >= 0.5患者样本的集落形成能力显著降低（P < 0.001）。基于rna的FLT3-ITD测量被推荐用于风险分层，AR与flt3靶向治疗资格的相关性值得进一步研究。
Controversy exists whether internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3-internal tandem duplication [ITD]) allelic ratio (AR) and/or length of the ITD should be taken into account for risk stratification of pediatric acute myeloid leukemia (AML) and whether it should be measured on RNA or DNA. Moreover, the ITD status may be of relevance for selecting patients eligible for FLT3 inhibitors. Here, we included 172 pediatric AML patients, of whom 36 (21%) harbored FLT3-ITD as determined on both RNA and DNA. Although there was a good correlation between both parameters AR(spearman) = 0.62 (95% confidence interval, 0.22-0.87) and ITDlength(spearman) = 0.98 (95% confidence interval, 0.90-1.00), only AR >= 0.5 and length >= 48 base pairs (bps) based on RNA measurements were significantly associated with overall survival (AR: P-logrank = .008; ITDlength: P-logrank = .011). In large ITDs (>156 bp on DNA) a remarkable 90-bp difference exists between DNA and RNA, including intron 14, which is spliced out in RNA. Ex vivo exposure (n = 30) to FLT3 inhibitors, in particular to the FLT3-specific inhibitor gilteritinib, showed that colony-forming capacity was significantly more reduced in FLT3-ITD-AR >= 0.5 compared with ITD-AR-low and ITD2 patient samples (P < .001). RNA-based FLT3-ITD measurements are recommended for risk stratification, and the relevance of AR regarding eligibility for FLT3-targeted therapy warrants further study.