文章：

FLT3-ITD突变急性髓系白血病的特征：白血病前体细胞的分子谱分析

Characterization of FLT3-ITDmut acute myeloid leukemia: molecular profiling of leukemic precursor cells

原文发布日期：2020-08-25

DOI: 10.1038/s41408-020-00352-9

类型: Article

开放获取: 是

英文摘要：

Acute myeloid leukemia (AML) with FLT3-ITD mutations (FLT3-ITDmut) remains a therapeutic challenge, with a still high relapse rate, despite targeted treatment with tyrosine kinase inhibitors. In this disease, the CD34/CD123/CD25/CD99+ leukemic precursor cells (LPCs) phenotype predicts for FLT3-ITD-positivity. The aim of this study was to characterize the distribution of FLT3-ITD mutation in different progenitor cell subsets to shed light on the subclonal architecture of FLT3-ITDmut AML. Using high-speed cell sorting, we sequentially purified LPCs and CD34+ progenitors in samples from patients with FLT3-ITDmut AML (n = 12). A higher FLT3-ITDmut load was observed within CD34/CD123/CD25/CD99+ LPCs, as compared to CD34+ progenitors (CD123+/−,CD25−,CD99low/−) (p = 0.0005) and mononuclear cells (MNCs) (p < 0.0001). This was associated with significantly increased CD99 mean fluorescence intensity in LPCs. Significantly higher FLT3-ITDmut burden was also observed in LPCs of AML patients with a small FLT3-ITDmut clones at diagnosis. On the contrary, the mutation burden of other myeloid genes was similar in MNCs, highly purified LPCs and/or CD34+ progenitors. Treatment with an anti-CD99 mAb was cytotoxic on LPCs in two patients, whereas there was no effect on CD34+ cells from healthy donors. Our study shows that FLT3-ITD mutations occur early in LPCs, which represent the leukemic reservoir. CD99 may represent a new therapeutic target in FLT3-ITDmut AML.
 

摘要翻译： 

尽管有酪氨酸激酶抑制剂的靶向治疗，携带FLT3-ITD突变的急性髓系白血病（AML）仍然是一个治疗挑战，复发率仍然很高。在这种疾病中，CD34/CD123/CD25/CD99+ 白血病前体细胞（LPCs）表型可预测FLT3-ITD阳性。本研究的目的是表征FLT3-ITD突变在不同祖细胞亚群中的分布，以揭示FLT3-ITDmut AML的亚克隆结构。使用高速细胞分选技术，我们依次从FLT3-ITDmut AML患者样本（n=12）中纯化了LPCs和CD34+祖细胞。与CD34+祖细胞（CD123+/−,CD25−,CD99low/−）相比（p=0.0005），以及单核细胞（MNCs）相比（p<0.0001），在CD34/CD123/CD25/CD99+ LPCs中观察到更高的FLT3-ITDmut负荷。这与LPCs中CD99平均荧光强度显著增加相关。在诊断时具有小FLT3-ITDmut克隆的AML患者中，LPCs中也观察到显著更高的FLT3-ITDmut负担。相反，其他髓系基因的突变负担在MNCs、高度纯化的LPCs和/或CD34+祖细胞中相似。使用抗CD99单克隆抗体治疗对两名患者的LPCs具有细胞毒性，而对健康供体的CD34+细胞没有影响。我们的研究表明，FLT3-ITD突变发生在LPCs早期，这些细胞代表白血病库。CD99可能代表FLT3-ITDmut AML的一个新治疗靶点。

原文链接：

Characterization of FLT3-ITDmut acute myeloid leukemia: molecular profiling of leukemic precursor cells