Differential effects of Vav‐promoter‐driven overexpression of BCLX and BFL1 on lymphocyte survival and B cell lymphomagenesis

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 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.

Mouse Models of c-myc Deregulation Driven by IgH Locus Enhancers as Models of B-Cell Lymphomagenesis

“…Using these mice clearly demonstrated the importance of numerous (new and well-known) tumor suppressor genes (such as FoxO3, CDK4, Mtap, and Smchd1) (19)(20)(21)(22). This model reinforced our knowledge concerning the signaling/regulation of the B-cell apoptotic program (members of the Bcl-2 family of apoptosis regulator) and deficiencies in apoptotic pathways leading to B-cell lymphomagenesis (23)(24)(25)(26)(27)(28). To our knowledge the influence of genetic background in the development of Bcell lymphomas in Eµ-Myc mice has not been documented.…”

Last but not least: BFL-1 as an emerging target for anti-cancer therapies

“…Following these discoveries, in 1996, it was found that BFL-1 can suppress p53-induced apoptosis like other Bcl-2 family members, clarifying its role as a pro-survival protein involved in apoptosis regulation [ 6 ]. Like overexpression of the other pro-survival proteins BCL-2, MCL-1, BCL-XL and BCL-W, overexpression of BFL-1 has been shown to accelerate MYC-driven myeloid leukemogenesis [ 7 ], as well as MYC-driven lymphomagenesis in the Eµ-Myc mouse model of B cell lymphoma [ 8 ].…”

Selective Inhibition of BFL1: It’s All about Finding the Right Partner

“…BFL1 is normally expressed in a tissuerestricted manner, with particularly high expression in certain hematopoietic cell lineages (Vogler, 2012). In addition to promoting normal hematopoiesis, BFL1 has been shown to accelerate development of Myc-driven murine lymphoma (Tuzlak et al, 2018) and mutant BRAF-driven melanoma (Haq et al, 2013). Importantly, BFL1 expression is activated by several transcription factors implicated in oncogenesis, including nuclear factor kB and MITF, leading to high BFL1 expression in acute and chronic leukemias, various lymphomas, melanomas, and cancers of the breast and colon (Correia et al, 2015;Haq et al, 2013;Vogler, 2012).…”