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Induction of Transcriptional Inhibitor Hairy and Enhancer of Split Homolog-1 and the Related Repression of Tumor-Suppressor Thioredoxin-Interacting Protein Are Important Components of Cell-Transformation Program Imposed by Oncogenic Kinase Nucleophosmin–Anaplastic Lymphoma Kinase

      Herein, we report that hairy and enhancer of split homolog-1 (HES1), known to repress gene transcription in progenitor cells of several cell lineages, is 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 structure analysis of the Orange domain of HES1 indicates that HES1 forms a highly stable homodimer. Of note, repression of HES1 expression leads to inhibition of ALK+ TCL cell growth in vivo. The expression of the HES1 gene is induced by NPM-ALK through activation of STAT3, which binds to the gene's promoter and induces the gene's transcription. NPM-ALK also directly phosphorylates HES1 protein. In turn, HES1 up-regulates and down-regulates in ALK+ TCL cell 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 is thioredoxin-interacting protein (TXNIP), encoding a protein implicated in promotion of cell death in various types of cells. Accordingly, ALK+ TCL cells and tissues lack expression of TXNIP, and its transcription is co-inhibited by HES1 and STAT3 in an NPM-ALK–dependent manner. Finally, the induced expression of TXNIP induces massive apoptotic cell death of ALK+ TCL cells. The results revealed 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.
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