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27 results on '"He, Bai‐Liang"'

4. Overcoming myelosuppression due to synthetic lethal toxicity for FLT3-targeted acute myeloid leukemia therapy.

Author

Warkentin, Alexander A, Lopez, Michael S, Lasater, Elisabeth A, Lin, Kimberly, He, Bai-Liang, Leung, Anskar Yh, Smith, Catherine C, Shah, Neil P, and Shokat, Kevan M

Subjects
Cell Line, Tumor, Animals, Zebrafish, Humans, Bone Marrow Diseases, Antineoplastic Agents, Structure-Activity Relationship, Mutation, Models, Biological, fms-Like Tyrosine Kinase 3, Leukemia, Myeloid, Acute, FLT3, KIT, biochemistry, chemical synthesis, human biology, leukemia, medicine, protein kinase, staurosporine, zebrafish, Orphan Drug, Hematology, Pediatric, Pediatric Cancer, Rare Diseases, Cancer, Clinical Research, Childhood Leukemia, 5.1 Pharmaceuticals, 6.1 Pharmaceuticals, Biochemistry and Cell Biology
Abstract

Activating mutations in FLT3 confer poor prognosis for individuals with acute myeloid leukemia (AML). Clinically active investigational FLT3 inhibitors can achieve complete remissions but their utility has been hampered by acquired resistance and myelosuppression attributed to a 'synthetic lethal toxicity' arising from simultaneous inhibition of FLT3 and KIT. We report a novel chemical strategy for selective FLT3 inhibition while avoiding KIT inhibition with the staurosporine analog, Star 27. Star 27 maintains potency against FLT3 in proliferation assays of FLT3-transformed cells compared with KIT-transformed cells, shows no toxicity towards normal human hematopoiesis at concentrations that inhibit primary FLT3-mutant AML blast growth, and is active against mutations that confer resistance to clinical inhibitors. As a more complete understanding of kinase networks emerges, it may be possible to define anti-targets such as KIT in the case of AML to allow improved kinase inhibitor design of clinical agents with enhanced efficacy and reduced toxicity.

Published
2014

10. Follistatin Alleviates Hepatic Steatosis in NAFLD via the mTOR Dependent Pathway

Author

Tong,Junlu, Cong,Li, Jia,Yingbin, He,Bai-Liang, Guo,Yifan, He,Jianzhong, Li,Decheng, Zou,Baojia, Li,Jian, Tong,Junlu, Cong,Li, Jia,Yingbin, He,Bai-Liang, Guo,Yifan, He,Jianzhong, Li,Decheng, Zou,Baojia, and Li,Jian

Abstract

Junlu Tong1,2 *, Li Cong1 *, Yingbin Jia,3 Bai-Liang He,4 Yifan Guo,1 Jianzhong He,5 Decheng Li,3 Baojia Zou,3 Jian Li3 1Department of Endocrinology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China; 2Department of Central Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China; 3Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China; 4Guangdong Provincial Key Laboratory of Biomedical Imaging, Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China; 5Department of Pathology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jian Li; Baojia Zou, Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China, Tel +86-756-252-8781, Email lijian5@mail.sysu.edu.cn; zoubj6@mail.sysu.edu.cnPurpose: 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

Published
2022

12. Transgenic IDH2R172Kand IDH2R140Qzebrafish models recapitulated features of human acute myeloid leukemia

Author

Wang, Dandan, Zheng, Lichuan, Cheng, Bowie Yik Ling, Sin, Chun-Fung, Li, Runsheng, Tsui, Sze Pui, Yi, Xinyu, Ma, Alvin Chun Hang, He, Bai Liang, Leung, Anskar Yu Hung, and Sun, Xuan

Abstract

Isocitrate dehydrogenase 2 (IDH2) mutations occur in more than 15% of cytogenetically normal acute myeloid leukemia (CN-AML) but comparative studies of their roles in leukemogenesis have been scarce. We generated zebrafish models of IDH2R172Kand IDH2R140QAML and reported their pathologic, functional and transcriptomic features and therapeutic responses to target therapies. Transgenic embryos co-expressing FLT3ITDand IDH2mutations showed accentuation of myelopoiesis. As these embryos were raised to adulthood, full-blown leukemia ensued with multi-lineage dysplasia, increase in myeloblasts and marrow cellularity and splenomegaly. The leukemia cells were transplantable into primary and secondary recipients and resulted in more aggressive disease. Tg(Runx1:FLT3ITDIDH2R172K) but not Tg(Runx1:FLT3ITDIDH2R140Q) zebrafish showed an increase in T-cell development at embryonic and adult stages. Single-cell transcriptomic analysis revealed increased myeloid skewing, differentiation blockade and enrichment of leukemia-associated gene signatures in both zebrafish models. Tg(Runx1:FLT3ITDIDH2R172K) but not Tg(Runx1:FLT3ITDIDH2R140Q) zebrafish showed an increase in interferon signals at the adult stage. Leukemic phenotypes in both zebrafish could be ameliorated by quizartinib and enasidenib. In conclusion, the zebrafish models of IDH2mutated AML recapitulated the morphologic, clinical, functional and transcriptomic characteristics of human diseases, and provided the prototype for developing zebrafish leukemia models of other genotypes that would become a platform for high throughput drug screening.

Published
2023
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13. Follistatin is a novel therapeutic target and biomarker in FLT 3/ ITD acute myeloid leukemia

Author

He, Bai‐Liang, primary, Yang, Ning, additional, Man, Cheuk Him, additional, Ng, Nelson Ka‐Lam, additional, Cher, Chae‐Yin, additional, Leung, Ho‐Ching, additional, Kan, Leo Lai‐Hok, additional, Cheng, Bowie Yik‐Ling, additional, Lam, Stephen Sze‐Yuen, additional, Wang, Michelle Lu‐Lu, additional, Zhang, Chun‐Xiao, additional, Kwok, Hin, additional, Cheng, Grace, additional, Sharma, Rakesh, additional, Ma, Alvin Chun‐Hang, additional, So, Chi Wai Eric, additional, Kwong, Yok‐Lam, additional, and Leung, Anskar Yu‐Hung, additional

Published
2020
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16. Follistatin is a novel therapeutic target and biomarker in FLT3/ITD acute myeloid leukemia.

Author

He, Bai‐Liang, Yang, Ning, Man, Cheuk Him, Ng, Nelson Ka‐Lam, Cher, Chae‐Yin, Leung, Ho‐Ching, Kan, Leo Lai‐Hok, Cheng, Bowie Yik‐Ling, Lam, Stephen Sze‐Yuen, Wang, Michelle Lu‐Lu, Zhang, Chun‐Xiao, Kwok, Hin, Cheng, Grace, Sharma, Rakesh, Ma, Alvin Chun‐Hang, So, Chi‐Wai Eric, Kwong, Yok‐Lam, and Leung, Anskar Yu‐Hung

Abstract

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]

Published
2020
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17. Whole exome sequencing identified candidate gene mutations in a pedigree of familial myeloproliferative neoplasm

Author

Cher, Chae Yin, primary, Lam Ng, Nelson Ka, additional, Yuen Lam, Stephen Sze, additional, He, Bai-Liang, additional, Ying, Dingge, additional, Hon-Yin Chung, Brian, additional, Au, Chun Hung, additional, Chan, Tsun Leung, additional, Kwan Ma, Edmond Shiu, additional, Suen Liang, Raymond Hin, additional, Kwong, Yok Lam, additional, and Hung Leung, Anskar Yu, additional

Published
2017
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19. Homoharringtonine (omacetaxine mepesuccinate) as an adjunct for FLT3 - ITD acute myeloid leukemia

Author

Lam, Stephen S. Y., primary, Ho, Eric S. K., additional, He, Bai-Liang, additional, Wong, Wui-Wing, additional, Cher, Chae-Yin, additional, Ng, Nelson K. L., additional, Man, Cheuk-Him, additional, Gill, Harinder, additional, Cheung, Alice M. S., additional, Ip, Ho-Wan, additional, So, Chi-Chiu, additional, Tamburini, Jerome, additional, So, Chi Wai Eric, additional, Ho, Dona N., additional, Au, Chun-Hang, additional, Chan, Tsun-Leung, additional, Ma, Edmond S. K., additional, Liang, Raymond, additional, Kwong, Yok-Lam, additional, and Leung, Anskar Y. H., additional

Published
2016
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27. A Zebrafish Model for Evaluating the Function of Human Leukemic Gene IDH1 and Its Mutation.

Author

Ma ACH, Shi X, He BL, Guo Y, and Leung AYH

Subjects
Animals, Embryo, Nonmammalian cytology, Hematopoiesis, High-Throughput Nucleotide Sequencing, Humans, Leukemia, Myeloid, Acute metabolism, Mutagenesis, Site-Directed, Phenotype, Zebrafish, Disease Models, Animal, Embryo, Nonmammalian metabolism, Isocitrate Dehydrogenase genetics, Leukemia, Myeloid, Acute genetics, Mutation
Abstract

The recent advent of next-generation sequencing (NGS) has greatly accelerated identification of gene mutations in myeloid malignancies at unprecedented speed that will soon outpace their functional validation by conventional laboratory techniques and animal models. A high-throughput whole-organism model is useful for the functional validation of new mutations. We recently reported the use of zebrafish to evaluate the hematopoietic function of isocitrate dehydrogenase 1 (IDH1) and the effects of expressing human IDH1-R132H that is frequently identified in human acute myeloid leukemia (AML), in myelopoiesis, with a view to develop zebrafish as a model of AML. Here, we use IDH1 as an example to describe a comprehensive approach to evaluate hematopoietic gene function and the effects of mutations using zebrafish as a model.

Published
2017
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