title: Convergence of the ZMIZ1 and NOTCH1 pathways at C-MYC in acute T lymphoblastic leukemias.
abstract: Activating NOTCH1 mutations are found in 50% to 60% of human T-cell acute lymphoblastic leukemia (T-ALL) samples. In mouse models, these mutations generally fail to induce leukemia. This observation suggests that NOTCH1 activation must collaborate with other genetic events. Mutagenesis screens previously implicated ZMIZ1 as a possible NOTCH1 collaborator in leukemia. ZMIZ1 is a transcriptional coactivator of the protein inhibitor of activated STAT (PIAS)-like family. Its role in oncogenesis is unknown. Here, we show that activated NOTCH1 and ZMIZ1 collaborate to induce T-ALL in mice. ZMIZ1 and activated NOTCH1 are coexpressed in a subset of human T-ALL patients and cell lines. ZMIZ1 inhibition slowed growth and sensitized leukemic cells to corticosteroids and NOTCH inhibitors. Gene expression profiling identified C-MYC, but not other NOTCH-regulated genes, as an essential downstream target of ZMIZ1. ZMIZ1 functionally interacts with NOTCH1 to promote C-MYC transcription and activity. The mechanism does not involve the NOTCH pathway and appears to be indirect and mediated independently of canonical PIAS functions through a novel N-terminal domain. Our study shows the importance of identifying genetic collaborations between parallel leukemic pathways that may be therapeutically targeted. They also raise new inquiries into potential NOTCH-ZMIZ1 collaboration in a variety of C-MYC-driven cancers.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Rakowski
authors.forename: Derek D
authors.initials: DD
authors.lastname: Garagiola
authors.forename: Choi M
authors.initials: CM
authors.lastname: Li
authors.forename: Margaret
authors.initials: M
authors.lastname: Decker
authors.forename: Sarah
authors.initials: S
authors.lastname: Caruso
authors.forename: Morgan
authors.initials: M
authors.lastname: Jones
authors.forename: Rork
authors.initials: R
authors.lastname: Kuick
authors.forename: Tomasz
authors.initials: T
authors.lastname: Cierpicki
authors.forename: Ivan
authors.initials: I
authors.lastname: Maillard
authors.forename: Mark Y
authors.initials: MY
authors.lastname: Chiang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D016259:Genes, myc; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D016601:RNA-Binding Proteins; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C497761:NOTCH1 protein, human; D016601:RNA-Binding Proteins; D051881:Receptor, Notch1; D014157:Transcription Factors; C480599:ZMIZ1 protein, human; C528563:Zimp10 protein, mouse