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

Abstract

Activating NOTCH1 mutations are found in 50–60% 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 co-activator 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 co-expressed 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 demonstrates 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.

Loss of Notch1-dependent p21Waf1/Cip1expression influences the Notch1 outcome in tumorigenesis

“…Several studies identify c-myc as an essential mediator of Notch1 signaling and show that Notch1 directly activates c-myc gene expression that integrates Notch1 activation with oncogenic signaling. [36][37][38] Interestingly, we found that c-myc expression is inhibited by GSI treatment in HaCaT-R (Fig. 7C).…”

Identification of a Novel Role of ZMIZ2 Protein in Regulating the Activity of the Wnt/β-Catenin Signaling Pathway

“…Specifically, ectopic expression of Zmiz1 in mice induces oncogenic transformation in cutaneous squamous cells (18). An interaction between the ZMIZ1 and NOTCH1 pathways has been implicated in promoting c-MYC activity in acute T lymphoblastic leukemia (19). Recently, we also explored the biological significance of ZMIZ2 in human tumorigenesis in a pilot experiment.…”

“…Ectopic expression of Zmiz1 in mice induces oncogenic transformation in cutaneous squamous cells (18). An interaction between the ZMIZ1 and NOTCH1 pathways has been implicated in promoting c-MYC activity in acute T lymphoblastic leukemia (19). Multiple lines of evidence suggest that there is no functional redundancy between ZMIZ1 and ZMIZ2 proteins during mouse early development (12,20).…”

Oncogenic Notch signaling in T-cell and B-cell lymphoproliferative disorders

“…Several resistance mechanisms are possible (reviewed in [43]). These mechanisms are frequently driven by oncogenic pathways that crosstalk with Notch signals, such as PI3K/mTOR (promoted by PTEN loss [83,84]) and MYC (promoted by FBWX7 loss [31,32], BRD4 [51,54] and ZMIZ1 [61,85]). A recent comprehensive investigation in Notch-induced mouse T-ALL revealed that GSI downregulated glycolysis and glutaminolysis, likely due to broad transcriptional effects on anabolic and catabolic genes [84].…”