American Association for Cancer Research
00085472can121389-sup-tab1.pdf (5.32 MB)

Supplementary Table 1 from Convergence of the ZMIZ1 and NOTCH1 Pathways at C-MYC in Acute T Lymphoblastic Leukemias

Download (5.32 MB)
journal contribution
posted on 2023-03-30, 22:00 authored by Lesley A. Rakowski, Derek D. Garagiola, Choi M. Li, Margaret Decker, Sarah Caruso, Morgan Jones, Rork Kuick, Tomasz Cierpicki, Ivan Maillard, Mark Y. Chiang

PDF file - 5445K, Table S1. Q-PCR primers used in this study.



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. Cancer Res; 73(2); 930–41. ©2012 AACR.