B-cell lymphoma-extra large alternative splicing (Bcl-x alternative splicing) (Bcl-x splicing)

B-cell lymphoma-extra large (Bcl-x) alternative splicing is a critical regulatory mechanism of the BCL2L1 gene that produces two isoforms with antagonistic roles in programmed cell death: the anti-apoptotic Bcl-xL and the pro-apoptotic Bcl-xS [1]. This process involves the selection of alternative 5' splice sites in exon 2, where the use of the downstream site generates Bcl-xL and the upstream site generates Bcl-xS [2]. In various malignancies, including lung, breast, and prostate cancers, the splicing balance is frequently shifted toward Bcl-xL, contributing to tumor progression and resistance to apoptosis-inducing therapies [3]. Therapeutic intervention aims to modulate this splicing event using splice-switching oligonucleotides (SSOs) or small molecules that target the splicing machinery to favor Bcl-xS production [4]. By decreasing the Bcl-xL/Bcl-xS ratio, these agents can sensitize cancer cells to chemotherapy or directly induce apoptosis [5]. However, therapeutic development must address challenges such as the risk of thrombocytopenia, as Bcl-xL is essential for platelet survival, and the need for efficient delivery systems to target tumor tissues specifically [6]. Sources: [1] UniProt P10415; [2] Shkreta et al. (2016) PMID: 27529205; [3] Mercatante et al. (2001) PMID: 11544173; [4] Bauman et al. (2010) PMID: 20433313; [5] Stevens et al. (2007) PMID: 17560371; [6] Mason et al. (2007) PMID: 17382880.

Other names

BCL2L1 alternative splicingBcl-xL/S splicingBcl-x splice site selectionBcl-x 5' splice site modulation

Modulation of alternative 5' splice site selection in the BCL2L1 gene to favor the production of the pro-apoptotic Bcl-xS isoform over the anti-apoptotic Bcl-xL isoform.