TY - JOUR
T1 - Follistatin is a novel therapeutic target and biomarker in FLT3/ITD acute myeloid leukemia
AU - He, Bai Liang
AU - Yang, Ning
AU - Man, Cheuk Him
AU - Ng, Nelson Ka Lam
AU - Cher, Chae Yin
AU - Leung, Ho Ching
AU - Kan, Leo Lai Hok
AU - Cheng, Bowie Yik Ling
AU - Lam, Stephen Sze Yuen
AU - Wang, Michelle Lu Lu
AU - Zhang, Chun Xiao
AU - Kwok, Hin
AU - Cheng, Grace
AU - Sharma, Rakesh
AU - Ma, Alvin Chun Hang
AU - So, Chi Wai Eric
AU - Kwong, Yok Lam
AU - Leung, Anskar Yu Hung
PY - 2020/4/7
Y1 - 2020/4/7
N2 - 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.
AB - 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.
KW - acute myeloid leukemia
KW - follistatin
KW - internal tandem duplication of Fms-like tyrosine kinase 3
UR - http://www.scopus.com/inward/record.url?scp=85082339245&partnerID=8YFLogxK
U2 - 10.15252/emmm.201910895
DO - 10.15252/emmm.201910895
M3 - Journal article
C2 - 32134197
AN - SCOPUS:85082339245
SN - 1757-4676
VL - 12
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 4
M1 - e10895
ER -