Follistatin is a novel therapeutic target and biomarker in FLT3/ITD acute myeloid leukemia.

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. Synopsis: FLT3/ITD is one of the most commonly mutated genes in acute myeloid leukemia, an aggressive hematological malignancy with poor prognosis. Here, embryonic morphogen FST is identified as a novel biomarker and therapeutic target for human FLT3/ITD‐mutated acute myeloid leukemia. The embryonic morphogen FST was overexpressed in FLT3/ITD‐expressing zebrafish, Flt3/ITD knock‐in mice and human FLT3/ITD AML.A novel FLT3/ITD‐p90RSK‐CREB‐FST signaling cascade was uncovered in human AML.FST is a novel therapeutic target and biomarker in FLT3/ITD AML. [ABSTRACT FROM AUTHOR]