Immunity
Volume 43, Issue 5, 17 November 2015, Pages 870-883
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Article
The PIAS-like Coactivator Zmiz1 Is a Direct and Selective Cofactor of Notch1 in T Cell Development and Leukemia

https://doi.org/10.1016/j.immuni.2015.10.007Get rights and content
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Highlights

  • Genetic inactivation of Zmiz1 inhibits T cell development and leukemogenesis

  • Zmiz1 inactivation does not affect intestinal homeostasis or myeloid suppression

  • Zmiz1 interacts directly with Notch1 through a tetratricopeptide repeat domain

  • Zmiz1 selectively binds and regulates Notch1 target genes, particularly Myc

Summary

Pan-NOTCH inhibitors are poorly tolerated in clinical trials because NOTCH signals are crucial for intestinal homeostasis. These inhibitors might also promote cancer because NOTCH can act as a tumor suppressor. We previously reported that the PIAS-like coactivator ZMIZ1 is frequently co-expressed with activated NOTCH1 in T cell acute lymphoblastic leukemia (T-ALL). Here, we show that similar to Notch1, Zmiz1 was important for T cell development and controlled the expression of certain Notch target genes, such as Myc. However, unlike Notch, Zmiz1 had no major role in intestinal homeostasis or myeloid suppression. Deletion of Zmiz1 impaired the initiation and maintenance of Notch-induced T-ALL. Zmiz1 directly interacted with Notch1 via a tetratricopeptide repeat domain at a special class of Notch-regulatory sites. In contrast to the Notch cofactor Maml, which is nonselective, Zmiz1 was selective. Thus, targeting the NOTCH1-ZMIZ1 interaction might combat leukemic growth while avoiding the intolerable toxicities of NOTCH inhibitors.

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