Internal tandem duplication of Fms-like tyrosine kinase 3 (FLT3/ITD) occurs in about 30% of acute myeloid leukemia (AML) and is associated with poor response to conventional treatment and adverse outcome. Here, we reported that human FLT3/ITD expression led to axis duplication and dorsalization in about 50% of zebrafish embryos. The morphologic phenotype was accompanied by ectopic expression of a morphogen follistatin (fst) during early embryonic development. Increase in fst expression also occurred in adult FLT3/ITD-transgenic zebrafish, Flt3/ITD knock-in mice, and human FLT3/ITD AML cells. Overexpression of human FST317 and FST344 isoforms enhanced clonogenicity and leukemia engraftment in xenotransplantation model via RET, IL2RA, and CCL5 upregulation. Specific targeting of FST by shRNA, CRISPR/Cas9, or antisense oligo inhibited leukemic growth in vitro and in vivo. Importantly, serum FST positively correlated with leukemia engraftment in FLT3/ITD AML patient-derived xenograft mice and leukemia blast percentage in primary AML patients. In FLT3/ITD AML patients treated with FLT3 inhibitor quizartinib, serum FST levels correlated with clinical response. These observations supported FST as a novel therapeutic target and biomarker in FLT3/ITD AML.

中文翻译：

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Follistatin 是 FLT3/ITD 急性髓系白血病的新型治疗靶点和生物标志物。


Fms 样酪氨酸激酶 3 (FLT3/ITD) 的内部串联重复发生在约 30% 的急性髓系白血病 (AML) 中，并且与常规治疗反应不佳和不良结果相关。在这里，我们报道人类 FLT3/ITD 表达导致约 50% 的斑马鱼胚胎轴重复和背侧化。在早期胚胎发育过程中，形态表型伴随着形态发生素卵泡抑素（fst）的异位表达。 fst 表达的增加也出现在成年 FLT3/ITD 转基因斑马鱼、Flt3/ITD 敲入小鼠和人类 FLT3/ITD AML 细胞中。人 FST317 和 FST344 亚型的过度表达通过 RET、IL2RA 和 CCL5 上调增强异种移植模型中的克隆形成和白血病植入。 shRNA、CRISPR/Cas9 或反义寡核苷酸特异性靶向 FST 可在体外和体内抑制白血病生长。重要的是，血清 FST 与 FLT3/ITD AML 患者来源的异种移植小鼠中的白血病植入以及原发性 AML 患者中的白血病母细胞百分比呈正相关。在接受 FLT3 抑制剂 quizartinib 治疗的 FLT3/ITD AML 患者中，血清 FST 水平与临床反应相关。这些观察结果支持 FST 作为 FLT3/ITD AML 的新治疗靶点和生物标志物。