Alternative splicing of the tumor suppressor ASPP2 results in a stress-inducible, oncogenic isoform prevalent in acute leukemia

Background: Apoptosis-stimulating Protein of TP53-2 (ASPP2) is a tumor suppressor enhancing TP53-mediated apoptosis via binding to the TP53 core domain. TP53 mutations found in cancers disrupt ASPP2 binding, arguing for an important role of ASPP2 in TP53-mediated tumor suppression. We now identify an oncogenic splicing variant, ASPP2 kappa, with high prevalence in acute leukemia. Methods: An mRNA screen to detect ASPP2 splicing variants was performed and ASPP2 kappa was validated using isoform-specific PCR approaches. Translation into a genuine protein isoform was evaluated after establishing epitope-specific antibodies. For functional studies cell models with forced expression of ASPP2 kappa or isoform-specific ASPP2 kappa-interference were created to evaluate proliferative, apoptotic and oncogenic characteristics of ASPP2 kappa. Findings: Exon skipping generates a premature stop codon, leading to a truncated C-terminus, omitting the TP53-binding sites. ASPP2 kappa translates into a dominant-negative protein variant impairing TP53-dependent induction of apoptosis. ASPP2 kappa is expressed in CD34+ leukemic progenitor cells and functional studies argue for a role in early oncogenesis, resulting in perturbed proliferation and impaired induction of apoptosis, mitotic failure and chromosomal instability (CIN) - similar to TP53 mutations. Importantly, as expression of ASPP2 kappa is stress-inducible it defines a novel class of dynamic oncogenes not represented by genomic mutations. Interpretation: Our data demonstrates that ASPP2 kappa plays a distinctive role as an antiapoptotic regulator of the TP53 checkpoint, rendering cells to a more aggressive phenotype as evidenced by proliferation and apoptosis rates - and ASPP2 kappa expression results in acquisition of genomic mutations, a first initiating step in leukemogenesis. We provide proof-of-concept to establish ASPP2 kappa as a clinically relevant biomarker and a target for molecule-defined therapy. (C) 2019 Published by Elsevier B.V.