The PIAS-like Coactivator Zmiz1 Is a Direct and Selective Cofactor of Notch1 in T Cell Development and Leukemia

• Published in: Immunity (Cambridge, Mass.) Mass.), 2015-11, Vol.43 (5), p.870-883
• Main Authors: Pinnell, Nancy, Yan, Ran, Cho, Hyo Je, Keeley, Theresa, Murai, Marcelo J., Liu, Yiran, Alarcon, Amparo Serna, Qin, Jason, Wang, Qing, Kuick, Rork, Elenitoba-Johnson, Kojo S.J., Maillard, Ivan, Samuelson, Linda C., Cierpicki, Tomasz, Chiang, Mark Y.
• Format: Article
• Language: English
• Subjects: Animals; Cancer; Cancer therapies; Cell Differentiation - physiology; Cell growth; Cell Line, Tumor; Deoxyribonucleic acid; DNA; Gene expression; Homeostasis; Humans; Jurkat Cells; Leukemia; Leukemia - metabolism; Leukemia - pathology; Lymphocytes; Mice; Mice, Inbred C57BL; Mutation; Pediatrics; Protein Inhibitors of Activated STAT - metabolism; Proteins; Receptor, Notch1 - metabolism; Signal Transduction - physiology; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; Transcription Factors - metabolism
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2015.10.007

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. [Display omitted] •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 Selective targeting of Notch functions therapeutically has been challenging. Chiang and colleagues find that the PIAS-like coactivator Zmiz1 is a direct, selective cofactor of Notch1. Zmiz1 inhibition affects Notch-mediated T cell development and leukemia, but does not affect intestinal homeostasis or myeloid suppression, indicating that Notch functions are biochemically separable.