SET alpha and SET beta mRNA isoforms in chronic lymphocytic leukaemia

SummaryAlteration in RNA splicing is implicated in carcinogenesis and progression. Mutations in spliceosome genes and alternative splicing of other genes have been noted in chronic lymphocytic leukaemia (CLL), a common B cell malignancy with heterogeneous outcomes. We previously demonstrated that differences in the amount of SET oncoprotein (a physiological inhibitor of the serine/threonine phosphatase, PP2A) is associated with clinical aggressiveness in patients with CLL. It is unknown if alternative splicing of gene transcripts regulating kinases and phosphatases affects disease pathobiology and CLL progression. We show here for the first time that mRNA levels of the alternatively spliced SET isoforms,SETA andSETB (SET α and SETβ), significantly correlate with disease severity (overall survival and time‐to‐first‐treatment) in CLL patients. In addition, we demonstrate that relative increase ofSETA toSETB mRNA can discriminate patients with a more aggressive disease course within the otherwise favourable CLL risk classifications ofIGHV mutated and favourable hierarchical fluorescencein  situ hybridisation groups. We validate our finding by showing comparable relationships ofSET mRNA with disease outcomes using samples from an independent CLL cohort from a separate institution. These findings indicate that alternative splicing ofSET, and potentially other signalling cascade molecules, influences CLL biology and patient outcomes.

Source: British Journal of Haematology - November 15, 2018 Category: Hematology Authors: Danielle M. Brander, Daphne R. Friedman, Alicia D. Volkheimer, Dale J. Christensen, Laura Z. Rassenti, Thomas J. Kipps, Eross Guadalupe, Youwei Chen, Dadong Zhang, Xi Wang, Carter Davis, Kouros Owzar, J. Brice Weinberg Tags: Research Paper Source Type: research