British Journal of Haematology | 2019
Post‐translational regulation could determine functional differences between SET alpha and beta isoforms in chronic lymphocytic leukaemia
Abstract
The recently published work by Brander and colleagues provides novel relevant findings about the clinical impact of SETalpha and SET-beta isoforms in chronic lymphocytic leukaemia (CLL) (Brander et al, 2019). The authors measured mRNA expression of these alternative SET splicing isoforms in a cohort of CLL, and the results were later confirmed in an independent cohort. Of importance, increased levels of SETA relative to SETB were found to be associated with CLL aggressiveness since those cases with a high SETA/SETB ratio showed significantly shorter overall survival and time-to-first-treatment. These results highlight that, very probably, SET isoforms show relevant functional differences in the tumour cell. In a previous work, our group described that SETBP1 binds and protects SET from the protease cleavage increasing the amount of full-length SET protein and decreasing short SET processed forms of 27, 24 and 20 kDa, which resulted in a stronger PP2A inhibition (Crist obal et al, 2010). Interestingly, we performed a time-course experiment ectopically expressing a SETGFP fusion protein in order to demonstrate that those short SET forms were products of a post-translational processing of the SET full-length protein. However, the plasmidic vector used included the SET-beta isoform and the products detected were exactly similar to those observed in the endogenous protein. These observations would indicate that the short SET forms observed could be products from the SET-beta isoform. This issue could explain that increased SET-alpha associates with progression and poor outcome since the uncleaved SET-alpha would enhance the inhibition of the tumour suppressor PP2A. Furthermore, it has been reported that phosphorylation of SET-beta on its Ser9, just in the centre of a nuclear localization signal, inhibits SET nuclear import and promotes its cytoplasmic detention, thereby enhancing the inhibition of PP2A (Yu et al, 2013). Considering that this region is located in the N-terminal extreme of the SET protein that it is just distinct in alpha and beta isoforms, it would be very interesting to test potential differences in their subcellular location and role as PP2A inhibitors. In conclusion, the functional differences of SET isoforms as well as the molecular regulatory mechanisms responsible for SET alternative splicing have to be fully clarified in forthcoming studies in order to improve the clinical and therapeutic usefulness of SET as a novel emerging molecular target in many solid tumours and leukaemias.