Premium
Differential effects of Vav‐promoter‐driven overexpression of BCLX and BFL1 on lymphocyte survival and B cell lymphomagenesis
Author(s) -
Tuzlak Selma,
Haschka Manuel D.,
Mokina AnnaMaria,
Rülicke Thomas,
Cory Suzanne,
Labi Verena,
Villunger Andreas
Publication year - 2018
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14426
Subject(s) - transgene , haematopoiesis , genetically modified mouse , biology , cancer research , apoptosis , gene , immunology , microbiology and biotechnology , stem cell , genetics
Overexpression of BCLX and BFL1/A1 has been reported in various human malignancies and is associated with poor prognosis and drug resistance, identifying these prosurvival BCL2 family members as putative drug targets. We have generated transgenic mice that express human BFL1 or human BCLX protein throughout the haematopoietic system under the control of the Vav gene promoter. Haematopoiesis is normal in both the Vav‐BFL1 and Vav‐BCLX transgenic (TG) mice and susceptibility to spontaneous haematopoietic 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 Eμ‐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/Eμ‐MYC double‐transgenic compared to Vav‐BFL1 mice, even during the preleukaemic 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.