Differential effects of Vav-promoter-driven overexpression of BCLX and BFL1 on lymphocyte survival and B cell lymphomagenesis
- Author(s)
- Tuzlak, S; Haschka, MD; Mokina, AM; Rulicke, T; Cory, S; Labi, V; Villunger, A;
- Details
- Publication Year 2018-03-02,Volume 285,Issue #8,Page 1403-1418
- Journal Title
- FEBS Journal
- Publication Type
- Journal Article
- Abstract
- Overexpression of BCLX and BFL1/A1 has been reported in various human malignancies and is associated with poor prognosis and drug-resistance, identifying these pro-survival BCL2 family members as putative drug-targets. We have generated transgenic mice that express human BFL1 or human BCLX protein throughout the hematopoietic system under the control of the Vav-gene promoter. Hematopoiesis is normal in both the Vav-BFL1 and Vav-BCLX transgenic (TG) mice and susceptibility to spontaneous hematopoietic malignancies is not increased. Lymphoid cells from Vav-BCLX TG mice exhibit increased resistance to apoptosis in vitro while most blood cell types form Vav-BFL1 TG mice were poorly protected. Both transgenes significantly accelerated lymphomagenesis in Emu-MYC TG mice and, surprisingly, the Vav-BFL1 transgene was the more potent. Unexpectedly, expression of transgenic BFL1 RNA and protein is significantly elevated in B lymphoid cells of Vav-BFL1/Emu-MYC DT compared to Vav-BFL1 mice, even during the pre-leukemic phase, providing a rationale for the potent synergy. In contrast, Vav-BCLX expression was not notably different. These mouse models of BFL1 and BCLX overexpression in lymphomas should be useful tools for the testing the efficacy of novel human BFL1- and BCLX-specific inhibitors. This article is protected by copyright. all rights reserved.
- Publisher
- Wiley
- Research Division(s)
- Molecular Genetics Of Cancer
- PubMed ID
- 29498802
- Publisher's Version
- https://doi.org/10.1111/febs.14426
- Open Access at Publisher's Site
https://doi.org/10.1111/febs.14426- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2018-07-09 02:07:34
Last Modified: 2018-07-09 02:17:47