Induction of Transcriptional Inhibitor HES1 and the Related Repression of Tumor-Suppressor TXNIP Are Important Components of Cell-Transformation Program Imposed by Oncogenic Kinase NPM-ALK.

Autor:	Zhang Q; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Wang HY; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Nayak A; Department of Biological Sciences, National University of Singapore, Singapore., Nunez-Cruz S; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Slupianek A; Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Liu X; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Basappa J; Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Fan JS; Department of Biological Sciences, National University of Singapore, Singapore., Chekol S; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Nejati R; Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Bogusz AM; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Turner SD; Department of Pathology, University of Cambridge, Cambridge, United Kingdom., Swaminathan K; Department of Biological Sciences, National University of Singapore, Singapore., Wasik MA; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania; Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: mariusz.wasik@fccc.edu.
Jazyk:	angličtina
Zdroj:	The American journal of pathology [Am J Pathol] 2022 Aug; Vol. 192 (8), pp. 1186-1198. Date of Electronic Publication: 2022 May 28.
DOI:	10.1016/j.ajpath.2022.05.005
Abstrakt:	This study reports that hairy and enhancer of split homolog-1 (HES1), known to repress gene transcription in progenitor cells of several cell lineages, was strongly expressed in cells and tissues of T-cell lymphoma expressing the oncogenic chimeric tyrosine kinase nucleophosmin (NPM)-anaplastic lymphoma kinase [ALK; ALK + T-cell lymphoma (TCL)]. The structural analysis of the Orange domain of HES1 indicated that HES1 formed a highly stable homodimer. Of note, repression of HES1 expression led to inhibition of ALK + TCL cell growth in vivo. The expression of the HES1 gene was induced by NPM-ALK through activation of STAT3, which bound to the gene's promoter and induced the gene's transcription. NPM-ALK also directly phosphorylated HES1 protein. In turn, HES1 up-regulated and down-regulated in ALK + TCL cells, the expression of numerous genes, protein products of which are involved in key cell functions, such as cell proliferation and viability. Among the genes inhibited by HES1 was thioredoxin-interacting protein (TXNIP), encoding a protein implicated in promotion of cell death in various types of cells. Accordingly, ALK + TCL cells and tissues lacked expression of TXNIP, and its transcription was co-inhibited by HES1 and STAT3 in an NPM-ALK-dependent manner. Finally, the induced expression of TXNIP induced massive apoptotic cell death of ALK + TCL cells. The results reveal a novel NPM-ALK-controlled pro-oncogenic regulatory network and document an important role of HES and TXNIP in the NPM-ALK-driven oncogenesis, with the former protein displaying oncogenic and the latter tumor suppressor properties. (Copyright © 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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