Convergence of the ZMIZ1 and NOTCH1 pathways at C-MYC in acute T lymphoblastic leukemias.
Cancer Res, 2013/1/15;73(2):930-41.
Rakowski LA[1], Garagiola DD, Li CM, Decker M, Caruso S, Jones M, Kuick R, Cierpicki T, Maillard I, Chiang MY
Affiliations
PMID: 23161489DOI: 10.1158/0008-5472.CAN-12-1389
Impact factor: 13.312
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.
MeSH terms
Animals; Cell Line, Tumor; Gene Expression Regulation; Genes, myc; Humans; Intracellular Signaling Peptides and Proteins; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; RNA-Binding Proteins; Receptor, Notch1; Signal Transduction; Transcription Factors
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