Discovery of a Novel CIP2A Variant (NOCIVA) with Clinical Relevance in Predicting TKI Resistance in Myeloid Leukemias.

PURPOSE

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein that inhibits the tumor suppressor PP2A-B56α. However, mRNA variants remain uncharacterized. Here, we report the discovery of a splicing variant, novel CIP2A variant ().

EXPERIMENTAL DESIGN

Characterization of CIP2A variants was performed by both 3' and 5' rapid amplification of cDNA ends from cancer cells. The function of NOCIVA was assessed by structural and molecular biology approaches. Its clinical relevance was studied in an acute myeloid leukemia (AML) patient cohort and two independent chronic myeloid leukemia (CML) cohorts.

RESULTS

contains exons 1 to 13 fused to 349 nucleotides from intron 13. Intriguingly, the first 39 nucleotides of the -specific sequence are in the coding frame with exon 13 of and code for a 13-amino acid peptide tail nonhomologous to any known human protein sequence. Therefore, NOCIVA translates to a unique human protein. NOCIVA retains the capacity to bind to B56α, but, whereas CIP2A is predominantly a cytoplasmic protein, NOCIVA translocates to the nucleus. Indicative of prevalent alternative splicing from to in myeloid malignancies, AML and CML patient samples overexpress , but not mRNA. In AML, a high mRNA expression ratio is a marker for adverse overall survival. In CML, high expression is associated with inferior event-free survival among imatinib-treated patients, but not among patients treated with dasatinib or nilotinib.

CONCLUSIONS

We discovered a novel variant of the oncoprotein CIP2A and its clinical relevance in predicting tyrosine kinase inhibitor therapy resistance in myeloid leukemias.

©2021 American Association for Cancer Research.