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The PIAS-like Coactivator Zmiz1 Is a Direct and Selective Cofactor of Notch1 in T Cell Development and Leukemia
Nancy Pinnell1, Ran Yan2, Hyo Je Cho3
1Cancer Biology Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA.
Abstract:
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.
Insights
Targeting the NOTCH1-ZMIZ1 interaction may treat T-cell acute lymphoblastic leukemia (T-ALL) without the severe side effects of broad NOTCH inhibitors, as ZMIZ1 plays a key role in T-ALL but not in essential normal cell functions.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Pan-NOTCH inhibitors show poor tolerability in clinical trials due to NOTCH signaling's role in intestinal homeostasis and potential tumor suppressor functions.
- ZMIZ1, a PIAS-like coactivator, is frequently co-expressed with activated NOTCH1 in T-cell acute lymphoblastic leukemia (T-ALL).
Purpose of the Study:
- To investigate the role of ZMIZ1 in T-ALL and its relationship with NOTCH1 signaling.
- To explore the potential of targeting the NOTCH1-ZMIZ1 interaction as a therapeutic strategy for T-ALL.
Main Methods:
- Comparative analysis of ZMIZ1 and Notch1 functions in T-cell development and intestinal homeostasis.
- Assessment of ZMIZ1's role in the initiation and maintenance of Notch-induced T-ALL.
- Investigation of the direct interaction between ZMIZ1 and NOTCH1 using molecular assays.
Main Results:
- Zmiz1, similar to Notch1, is crucial for T-cell development and regulates target genes like Myc.
- Unlike Notch, Zmiz1 does not significantly impact intestinal homeostasis or myeloid suppression.
- Deletion of Zmiz1 hinders the development and progression of Notch-induced T-ALL.
- ZMIZ1 selectively interacts with NOTCH1 at specific regulatory sites, unlike the nonselective cofactor Maml.
Conclusions:
- ZMIZ1 is a selective cofactor for NOTCH1 in T-ALL, distinct from its role in normal tissue homeostasis.
- Targeting the NOTCH1-ZMIZ1 interaction presents a promising therapeutic avenue for T-ALL, potentially avoiding the toxicities associated with broad NOTCH inhibition.
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