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



Makela, Eleonora, Pavic, Karolina, Varila, Taru, Salmenniemi, Urpu, Loyttyniemi, Eliisa, Nagelli, Srikar G, Ammunet, Tea, Kahari, Veli-Matti, Clark, Richard E ORCID: 0000-0002-1261-3299, Elo, Laura L
et al (show 4 more authors) (2021) Discovery of a Novel CIP2A Variant (NOCIVA) with Clinical Relevance in Predicting TKI Resistance in Myeloid Leukemias. CLINICAL CANCER RESEARCH, 27 (10). pp. 2848-2860.

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Abstract

<h4>Purpose</h4>Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein that inhibits the tumor suppressor PP2A-B56α. However, <i>CIP2A</i> mRNA variants remain uncharacterized. Here, we report the discovery of a <i>CIP2A</i> splicing variant, novel CIP2A variant (<i>NOCIVA</i>).<h4>Experimental design</h4>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.<h4>Results</h4><i>NOCIVA</i> contains <i>CIP2A</i> exons 1 to 13 fused to 349 nucleotides from <i>CIP2A</i> intron 13. Intriguingly, the first 39 nucleotides of the <i>NOCIVA</i>-specific sequence are in the coding frame with exon 13 of <i>CIP2A</i> 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 <i>CIP2A</i> to <i>NOCIVA</i> in myeloid malignancies, AML and CML patient samples overexpress <i>NOCIVA</i>, but not <i>CIP2A</i> mRNA. In AML, a high <i>NOCIVA/CIP2A</i> mRNA expression ratio is a marker for adverse overall survival. In CML, high <i>NOCIVA</i> expression is associated with inferior event-free survival among imatinib-treated patients, but not among patients treated with dasatinib or nilotinib.<h4>Conclusions</h4>We discovered a novel variant of the oncoprotein CIP2A and its clinical relevance in predicting tyrosine kinase inhibitor therapy resistance in myeloid leukemias.

Item Type: Article
Uncontrolled Keywords: Humans, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Antineoplastic Combined Chemotherapy Protocols, Autoantigens, Protein Kinase Inhibitors, Prognosis, Treatment Outcome, Gene Expression Regulation, Leukemic, Alternative Splicing, Base Sequence, Protein Conformation, Structure-Activity Relationship, Drug Resistance, Neoplasm, Models, Molecular, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Leukemia, Myeloid, Acute, RNA Isoforms, Biomarkers, Tumor
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 19 Mar 2021 11:03
Last Modified: 08 Mar 2023 14:55
DOI: 10.1158/1078-0432.CCR-20-3679
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3117749