Follistatin is a novel therapeutic target and biomarker in
            <scp>FLT</scp>
            3/
            <scp>ITD</scp>
            acute myeloid leukemia

He, Ben; Yang, Ning; Man, Cheuk Him; Ng, Nelson Ka Lam; Cher, Chae Yin; Leung, Ho Ching; Kan, Leo Lai Hok; Cheng, Bowie Y.; Lam, Simon S. K.; Wang, Michelle Lu Lu; Zhang, Chun Xiao; Kwok, Harry; Cheng, Grace; Sharma, Rakesh; Hang, Alvin Chun; So, Chi Wai Eric; Kwong, Yok Lam; Leung, Anskar Yu Hung

doi:10.15252/emmm.201910895

Cited by 14 publications

(5 citation statements)

References 70 publications

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“…Previous studies have reported that ovarian cancer cells increase FST production in response to TGF-β stimulation ( 84 ), and FST expression has been shown to coincide with the activation of the signaling cascades downstream of EGF signaling in leukemia cells ( 85 ), however, signaling events driving FST in HNSCC cells remain unknown. Given the enrichment of the EGFR-TGF-β network in our dataset, we hypothesized that HNSCC cells might regulate FST expression in response to both signaling pathways.…”

Section: Resultsmentioning

confidence: 99%

An integrated genomic approach identifies follistatin as a target of the p63-epidermal growth factor receptor oncogenic network in head and neck squamous cell carcinoma

et al. 2023

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Although numerous putative oncogenes have been associated with the etiology of head and neck squamous cell carcinoma (HNSCC), the mechanisms by which these oncogenes and their downstream targets mediate tumor progression have not been fully elucidated. We performed an integrative analysis to identify a crucial set of targets of the oncogenic transcription factor p63 that are common across multiple transcriptomic datasets obtained from HNSCC patients, and representative cell line models. Notably, our analysis revealed FST which encodes follistatin, a secreted glycoprotein that inhibits the transforming growth factor TGFβ/activin signaling pathways, to be a direct transcriptional target of p63. In addition, we found that FST expression is also driven by epidermal growth factor receptor EGFR signaling, thus mediating a functional link between the TGF-β and EGFR pathways. We show through loss- and gain-of-function studies that FST predominantly imparts a tumor-growth and migratory phenotype in HNSCC cells. Furthermore, analysis of single-cell RNA sequencing data from HNSCC patients unveiled cancer cells as the dominant source of FST within the tumor microenvironment and exposed a correlation between the expression of FST and its regulators with immune infiltrates. We propose FST as a prognostic biomarker for patient survival and a compelling candidate mediating the broad effects of p63 on the tumor and its associated microenvironment.

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Section: Resultsmentioning

confidence: 99%

An integrated genomic approach identifies follistatin as a target of the p63-epidermal growth factor receptor oncogenic network in head and neck squamous cell carcinoma

et al. 2023

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“…In our study, the FLT3-ITD mutant patients were enriched for CD25+ AML cells, which has also been described previously by others ( 5 , 7 ). It is hypothesized that FLT3-ITD leads to the upregulation of RET , IL2RA and CCL5 through Follistatin ( 44 ), providing some mechanistic basis for the strong association between FLT3-ITD and CD25 expression.…”

Section: Discussionmentioning

confidence: 99%

CD25 targeting with the afucosylated human IgG1 antibody RG6292 eliminates regulatory T cells and CD25+ blasts in acute myeloid leukemia

Pousse

Korfi

Medeiros³

et al. 2023

Front. Oncol.

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BackgroundAcute Myeloid leukemia is a heterogeneous disease that requires novel targeted treatment options tailored to the patients’ specific microenvironment and blast phenotype.MethodsWe characterized bone marrow and/or blood samples of 37 AML patients and healthy donors by high dimensional flow cytometry and RNA sequencing using computational analysis. In addition, we performed ex vivo ADCC assays using allogeneic NK cells isolated from healthy donors and AML patient material to test the cytotoxic potential of CD25 Mab (also referred to as RG6292 and RO7296682) or isotype control antibody on regulatory T cells and CD25+ AML cells.ResultsBone marrow composition, in particular the abundance of regulatory T cells and CD25 expressing AML cells, correlated strongly with that of the blood in patients with time-matched samples. In addition, we observed a strong enrichment in the prevalence of CD25 expressing AML cells in patients bearing a FLT3-ITD mutation or treated with a hypomethylating agent in combination with venetoclax. We adopted a patient-centric approach to study AML clusters with CD25 expression and found it most highly expressed on immature phenotypes. Ex vivo treatment of primary AML patient samples with CD25 Mab, a human CD25 specific glycoengineered IgG1 antibody led to the specific killing of two different cell types, CD25+ AML cells and regulatory T cells, by allogeneic Natural Killer cells.ConclusionThe in-depth characterization of patient samples by proteomic and genomic analyses supported the identification of a patient population that may benefit most by harnessing CD25 Mab’s dual mode of action. In this pre-selected patient population, CD25 Mab could lead to the specific depletion of regulatory T cells, in addition to leukemic stem cells and progenitor-like AML cells that are responsible for disease progression or relapse.

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“…Lentivirus vectors encoding FST overexpression were prepared as described previously. 30 To establish stable FST-overexpressing LO2 cells, we transfected the cells with the pLJM1‐EGFP (#19319, Addgene, USA) lentivirus vector encoding human FST isoforms (FST317 and FST344). To establish stable FST-knockdown LO2 cells, we transfected the cells with lentivirus vector encoding short hairpin RNA targeting FST (FSTsh), which was designed and produced by Genechem Technology Company (Shanghai, China).…”

Section: Methodsmentioning

confidence: 99%

Follistatin Alleviates Hepatic Steatosis in NAFLD via the mTOR Dependent Pathway

Tong¹,

Cong²,

Jia³

et al. 2022

DMSO

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Purpose In this study, we aimed to investigate the effect of follistatin (FST) on hepatic steatosis in NAFLD and the underlying mechanism, which has rarely been reported before. Methods Liver samples from NAFLD patients and normal liver samples (from liver donors) were collected to investigate hepatic FST expression in humans. Additionally, human liver cells (LO2) were treated with free fatty acid (FFA) to induce lipid accumulation. Furthermore, lentivirus with FST overexpression or knockdown vectors were used to generate stable cell lines, which were subsequently treated with FFA or FFA and rapamycin. In the animal experiments, male C57BL/6J mice were fed with a high-fat diet (HFD) to induce NAFLD, after which the adeno-associated virus (AAV) gene vectors for FST overexpression were administered. In both cell culture and mice, we evaluated morphological changes and the protein expression of sterol regulatory element-binding protein1 (SREBP1), acetyl-CoA carboxylase1 (ACC1), carbohydrate-responsive element-binding protein (ChREBP), fatty acid synthase (FASN), and Akt/mTOR signaling. The body weight and serum parameters of the mice were also measured. Results Hepatic FST expression level was higher in NAFLD patients compared to normal samples. In LO2 cells, FST overexpression alleviated lipid accumulation and lipogenesis, whereas FST knockdown aggravated hepatic steatosis. FST could regulate Akt/mTOR signaling, and the mTOR inhibitor rapamycin abolished the effect of FST knockdown on hepatic de novo lipogenesis (DNL). Furthermore, FST expression was increased in HFD mice compared to the corresponding controls. FST overexpression in mice reduced body weight gain, hyperlipidemia, hepatic DNL, and suppressed Akt/mTOR signaling. Conclusion Hepatic FST expression increases in NAFLD and plays a protective role in hepatic steatosis. FST overexpression gene therapy alleviates hepatic steatosis via the mTOR pathway.Therefore, gene therapy for FST is a promising treatment in NAFLD.

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Follistatin is a novel therapeutic target and biomarker in FLT 3/ ITD acute myeloid leukemia

Cited by 14 publications

References 70 publications

An integrated genomic approach identifies follistatin as a target of the p63-epidermal growth factor receptor oncogenic network in head and neck squamous cell carcinoma

An integrated genomic approach identifies follistatin as a target of the p63-epidermal growth factor receptor oncogenic network in head and neck squamous cell carcinoma

CD25 targeting with the afucosylated human IgG1 antibody RG6292 eliminates regulatory T cells and CD25+ blasts in acute myeloid leukemia

Follistatin Alleviates Hepatic Steatosis in NAFLD via the mTOR Dependent Pathway

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