Abstract
ABSTRACTConditional deletion of RBP-J, the major transcriptional effector of Notch signaling, specifically within renin-expressing cells leads to the development of B-cell leukemia. However, the influence of contributing factors such as mouse strain, cell of origin and Cre recombinase copy number are unknown. In this study, we compared RBP-J deletion efficiency using one versus two copies of Cre recombinase. Further, we compared the incidence and timing of leukemia development in two unique strains of mice, C57BL/6 and 129/SV, as well as at different B-cell developmental stages. We found that animals expressing two copies of Cre recombinase developed B-cell leukemia at an earlier age and with more fulminant disease, compared with control animals and animals expressing one copy of Cre recombinase. In addition, we found a difference in leukemia incidence between C57BL/6 and 129/SV mouse strains. Whereas deletion of RBP-J in renin-expressing cells of C57BL/6 mice leads to the development of B-cell leukemia, 129/SV mice develop dermatitis with a reactive, myeloproliferative phenotype. The difference in phenotypes is explained, in part, by the differential expression of extra-renal renin; C57BL/6 mice have more renin-expressing cells within hematopoietic tissues. Finally, we found that deletion of RBP-J in Mb1- or CD19-expressing B lymphocytes does not result in leukemia development. Together, these studies establish that renin progenitors are vulnerable cells for neoplastic transformation and emphasize the importance of genetic background on the development of inflammatory and malignant conditions.This article has an associated First Person interview with the first author of the paper.
Highlights
The Notch signaling pathway is involved in a broad spectrum of cell-fate decisions, including self-renewal, lineage commitment and differentiation, within a variety of cell types
Influence of mouse strain and Cre recombinase copy number on leukemia development Previously, we reported that conditional deletion of RBP-J within renin-expressing cells leads to a highly penetrant and aggressive form of precursor B-cell leukemia (Belyea et al, 2014)
We found remarkable differences in leukemia incidence, severity and phenotype based on the strain of mouse, cell of origin and deletion efficiency
Summary
The Notch signaling pathway is involved in a broad spectrum of cell-fate decisions, including self-renewal, lineage commitment and differentiation, within a variety of cell types. Multiple studies have demonstrated that Notch signaling promotes T-cell commitment over B-cell fates from bi-potent lymphocyte progenitors. Later, during B-cell development, Notch signaling regulates marginal zone versus follicular B-cell fates in the spleen (Tanigaki et al, 2002, 2003). Given these important roles during lymphocyte development, Notch signaling must be tightly controlled. Activation of the Notch pathway appears to cause growth arrest in a wide range of B-cell malignancies (Zweidler-McKay et al, 2005)
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