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Published on: May 10, 2017
Characterization of two distinct lymphoproliferative diseases caused by ectopic expression of the Notch ligand DLL4
Huizhong Xiong1, Antonio Maraver2, Jo-Ann Latkowski3
1Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, New York, United States of America ; The Sackler Institute of Graduate Biomedical Sciences, New York University School of Medicine, New York, New York, United States of America.
Abstract:
Notch signaling is essential for the development of T cell progenitors through the interaction of NOTCH1 receptor on their surface with the ligand, Delta-like 4 (DLL4), which is expressed by the thymic epithelial cells. Notch signaling is quickly shut down once the cells pass β-selection, and CD4/CD8 double positive (DP) cells are unresponsive to Notch. Over the past two decades a number of papers reported that over-activation of Notch signaling causes T cell acute lymphoblastic leukemia (T-ALL), a cancer that prominently features circulating monoclonal CD4/CD8 double positive T cells in different mouse models. However, the possible outcomes of Notch over-activation at different stages of T cell development are unknown, and the fine timing of Notch signaling that results in T-ALL is poorly understood. Here we report, by using a murine model that ectopically expresses DLL4 on developing T cells, that the T-ALL onset is highly dependent on a sustained Notch activity throughout the DP stage, which induces additional mutations to further boost the signaling. In contrast, a shorter period of Notch activation that terminates at the DP stage causes a polyclonal, non-transmissible lymphoproliferative disorder that is also lethal. These observations resolved the discrepancy of previous papers on DLL4 driven hematological diseases in mice, and show the critical importance of the timing and duration of Notch activity.
Insights
Sustained Notch signaling during T cell development, particularly in CD4/CD8 double positive cells, drives T cell acute lymphoblastic leukemia (T-ALL). Shorter Notch activation leads to a different, lethal lymphoproliferative disorder.
Area of Science:
- Immunology
- Developmental Biology
- Cancer Biology
Background:
- Notch signaling, involving NOTCH1 and Delta-like 4 (DLL4), is crucial for T cell progenitor development.
- Over-activation of Notch signaling has been linked to T cell acute lymphoblastic leukemia (T-ALL).
- The precise timing and duration of Notch signaling in T cell development and its role in T-ALL remain unclear.
Purpose of the Study:
- To investigate the impact of Notch over-activation timing on T cell development and T-ALL onset.
- To elucidate the mechanisms by which sustained Notch activity leads to T-ALL.
- To resolve discrepancies in previous findings regarding DLL4-driven hematological diseases.
Main Methods:
- Utilized a murine model with ectopic DLL4 expression on developing T cells.
- Analyzed the effects of sustained versus transient Notch signaling during the CD4/CD8 double positive (DP) stage.
- Investigated the induction of additional mutations under sustained Notch activity.
Main Results:
- Sustained Notch activity throughout the DP stage promoted T-ALL by inducing further mutations.
- Transient Notch activation, terminating at the DP stage, resulted in a lethal polyclonal lymphoproliferative disorder.
- The timing and duration of Notch signaling critically influence disease outcomes.
Conclusions:
- T-ALL onset is dependent on sustained Notch signaling throughout the DP stage of T cell development.
- Transient Notch activation leads to a distinct, albeit lethal, lymphoproliferative disorder.
- This study clarifies the role of Notch signaling timing in T-ALL pathogenesis and hematological diseases.
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