AKIRA KAWASAKI
Email Address
nmiak@nus.edu.sg
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Publication Oncofetal gene SALL4 in aggressive hepatocellular carcinoma(2013) Yong, K.J.; Gao, C.; Lim, J.S.J.; Yan, B.; Yang, H.; Dimitrov, T.; Kawasaki, A.; Ong, C.W.; Wong, K.-F.; Lee, S.; Ravikumar, S.; Srivastava, S.; Tian, X.; Poon, R.T.; Fan, S.T.; Luk, J.M.; Dan, Y.Y.; Salto-Tellez, M.; Chai, L.; Tenen, D.G.; CANCER SCIENCE INSTITUTE OF SINGAPOREBACKGROUND: Hepatocellular carcinoma is the third leading cause of cancer-related deaths worldwide. In the heterogeneous group of hepatocellular carcinomas, those with characteristics of embryonic stem-cell and progenitor-cell gene expression are associated with the worst prognosis. The oncofetal gene SALL4, a marker of a subtype of hepatocellular carcinoma with progenitor-like features, is associated with a poor prognosis and is a potential target for treatment. METHODS: We screened specimens obtained from patients with primary hepatocellular carcinoma for the expression of SALL4 and carried out a clinicopathological analysis. Loss-of-function studies were then performed to evaluate the role of SALL4 in hepatocarcinogenesis and its potential as a molecular target for therapy. To assess the therapeutic effects of a peptide that targets SALL4, we used in vitro functional and in vivo xenograft assays. RESULTS: SALL4 is an oncofetal protein that is expressed in the human fetal liver and silenced in the adult liver, but it is reexpressed in a subgroup of patients who have hepatocellular carcinoma and an unfavorable prognosis. Gene-expression analysis showed the enrichment of progenitor-like gene signatures with overexpression of proliferative and metastatic genes in SALL4 -positive hepatocellular carcinomas. Loss-of-function studies confirmed the critical role of SALL4 in cell survival and tumorigenicity. Blocking SALL4-corepressor interactions released suppression of PTEN (the phosphatase and tensin homologue protein) and inhibited tumor formation in xenograft models in vivo. CONCLUSIONS: SALL4 is a marker for a progenitor subclass of hepatocellular carcinoma with an aggressive phenotype. The absence of SALL4 expression in the healthy adult liver enhances the potential of SALL4 as a treatment target in hepatocellular carcinoma. Copyright © 2013 Massachusetts Medical Society.Publication Elevated PIN1 expression by C/EBPα-p30 blocks C/EBPα-induced granulocytic differentiation through c-Jun in AML(2010) Pulikkan, J.A.; Dengler, V.; Peer, Zada A.A.; Geletu, M.; Behre, G.; Kawasaki, A.; Tenen, D.G.; Pasalic, Z.; Bohlander, S.K.; Ryo, A.; MEDICINE; CANCER SCIENCE INSTITUTE OF SINGAPOREPublication The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia(NATURE PUBLISHING GROUP, 2018-04-24) Numata, Akihiko; Kwok, Hui Si; Kawasaki, Akira; Li, Jia; Zhou, Qi-Ling; Kerry, Jon; Benoukraf, Touati; Bararia, Deepak; Li, Feng; Ballabio, Erica; Tapia, Marta; Deshpande, Aniruddha J; Welner, Robert S; Delwel, Ruud; Yang, Henry; Milne, Thomas A; Taneja, Reshma; Tenen, Daniel G; Assoc Prof Reshma Taneja; PHYSIOLOGY; CANCER SCIENCE INSTITUTE OF SINGAPORE© 2018 The Author(s). Acute Myeloid Leukemia (AML) with MLL gene rearrangements demonstrate unique gene expression profiles driven by MLL-fusion proteins. Here, we identify the circadian clock transcription factor SHARP1 as a novel oncogenic target in MLL-AF6 AML, which has the worst prognosis among all subtypes of MLL-rearranged AMLs. SHARP1 is expressed solely in MLL-AF6 AML, and its expression is regulated directly by MLL-AF6/DOT1L. Suppression of SHARP1 induces robust apoptosis of human MLL-AF6 AML cells. Genetic deletion in mice delays the development of leukemia and attenuated leukemia-initiating potential, while sparing normal hematopoiesis. Mechanistically, SHARP1 binds to transcriptionally active chromatin across the genome and activates genes critical for cell survival as well as key oncogenic targets of MLL-AF6. Our findings demonstrate the unique oncogenic role for SHARP1 in MLL-AF6 AML.Publication C/EBPa controls acquisition and maintenance of adult haematopoietic stem cell quiescence(2013-04) Ye, M.; Zhang, H.; Amabile, G.; Yang, H.; Staber, P.B.; Zhang, P.; Levantini, E.; Alberich-Jordà, M.; Zhang, J.; Kawasaki, A.; Tenen, D.G.; CANCER SCIENCE INSTITUTE OF SINGAPOREIn blood, the transcription factor C/EBPa is essential for myeloid differentiation and has been implicated in regulating self-renewal of fetal liver haematopoietic stem cells (HSCs). However, its function in adult HSCs has remained unknown. Here, using an inducible knockout model we found that C/EBPa-deficient adult HSCs underwent a pronounced increase in number with enhanced proliferation, characteristics resembling fetal liver HSCs. Consistently, transcription profiling of C/EBPa-deficient HSCs revealed a gene expression program similar to fetal liver HSCs. Moreover, we observed that age-specific Cebpa expression correlated with its inhibitory effect on the HSC cell cycle. Mechanistically we identified N-Myc as a downstream target of C/EBPa, and loss of C/EBPa resulted in de-repression of N-Myc. Our data establish C/EBPa as a central determinant in the switch from fetal to adult HSCs. © 2013 Macmillan Publishers Limited. All rights reserved.Publication Physicomechanical properties of porous materials by spark plasma sintering(Taylor & Francis, 2019-02-13) Abolfazl Azarniya; Amir Azarniya; Mir Saman Safavi; Mohammad Farshbaf Ahmadipour; Melica Esmaeeli Seraji; Saeed Sovizi; Mahboobe Saqaei; Ridvan Yamanoglu; Mohammad Soltaninejad; Hamid Reza Madaah Hosseini; Seeram Ramakrishna; Akira Kawasaki; Stefan Adams; M. V. Reddy; CANCER SCIENCE INSTITUTE OF SINGAPORE; MECHANICAL ENGINEERING; MATERIALS SCIENCE AND ENGINEERING