Open AccessFollistatin is a novel therapeutic target and biomarker in FLT 3/ ITD acute myeloid leukemia
Author(s) -
He BaiLiang,
Yang Ning,
Man Cheuk Him,
Ng Nelson KaLam,
Cher ChaeYin,
Leung HoChing,
Kan Leo LaiHok,
Cheng Bowie YikLing,
Lam Stephen SzeYuen,
Wang Michelle LuLu,
Zhang ChunXiao,
Kwok Hin,
Cheng Grace,
Sharma Rakesh,
Ma Alvin ChunHang,
So ChiWai Eric,
Kwong YokLam,
Leung Anskar YuHung
Publication year - 2020
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201910895
Subject(s) - hematology , china , medicine , traditional chinese medicine , oncology , library science , family medicine , political science , pathology , alternative medicine , computer science , law
Internal tandem duplication of Fms‐like tyrosine kinase 3 ( FLT 3 / 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 FLT 3 / 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 FLT 3 / ITD ‐transgenic zebrafish, Flt3 / ITD knock‐in mice, and human FLT 3 / ITD AML cells. Overexpression of human FST 317 and FST 344 isoforms enhanced clonogenicity and leukemia engraftment in xenotransplantation model via RET , IL 2 RA , and CCL 5 upregulation. Specific targeting of FST by sh RNA , CRISPR /Cas9, or antisense oligo inhibited leukemic growth in vitro and in vivo . Importantly, serum FST positively correlated with leukemia engraftment in FLT 3 / ITD AML patient‐derived xenograft mice and leukemia blast percentage in primary AML patients. In FLT 3 / ITD AML patients treated with FLT 3 inhibitor quizartinib, serum FST levels correlated with clinical response. These observations supported FST as a novel therapeutic target and biomarker in FLT 3 / ITD AML .