Notch signaling promotes disease initiation and progression in murine chronic lymphocytic leukemia

Delphine Tardivon, Mateusz Antoszewski, Nadine Zangger, Marianne Nkosi, Jessica Sordet-Dessimoz, Rudi Hendriks, Ute Koch, Freddy Radtke*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Scopus)

Abstract

NOTCH1 gain-of-function mutations are recurrent in B-cell chronic lymphocytic leukemia (B-CLL), where they are associated with accelerated disease progression and refractoriness to chemotherapy. The specific role of NOTCH1 in the development and progression of this malignancy is unclear. Here, we assess the impact of loss of Notch signaling and pathway hyperactivation in an in vivo mouse model of CLL (IgH.TEμ) that faithfully replicates many features of the human pathology. Ablation of canonical Notch signaling using conditional gene inactivation of RBP-J in immature hematopoietic or B-cell progenitors delayed CLL induction and reduced incidence of mice developing disease. In contrast, forced expression of a dominant active form of Notch resulted in more animals developing CLL with early disease onset. Comparative analysis of gene expression and epigenetic features of Notch gain-of-function and control CLL cells revealed direct and indirect regulation of cell cycle–associated genes, which led to increased proliferation of Notch gain-of-function CLL cells in vivo. These results demonstrate that Notch signaling facilitates disease initiation and promotes CLL cell proliferation and disease progression.

Original languageEnglish
Pages (from-to)3079-3092
Number of pages14
JournalBlood
Volume137
Issue number22
DOIs
Publication statusPublished - 3 Jun 2021

Bibliographical note

Funding Information:
This work was in part supported by the Swiss National Science Foundation and the Swiss Cancer League (F.R.).

Publisher Copyright:
© 2021 American Society of Hematology

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