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

A1 Refereed original research article in a scientific journal

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

Authors: Mäkelä Eleonora, Pavic Karolina, Varila Taru, Salmenniemi Urpu, Löyttyniemi Eliisa, Nagelli Srikar G., Ammunét Tea, Kähäri Veli-Matti, Clark Richard E., Elo Laura L., Bachanaboyina Venkata Kumari, Lucas Claire M., Itälä-Remes Maija, Westermarck Jukka

Publisher: AMER ASSOC CANCER RESEARCH

Publication year: 2021

Journal: Clinical Cancer Research

Journal acronym: CLIN CANCER RES

Volume: 27

Issue: 10

First page : 2848

Last page: 2860

Number of pages: 13

ISSN: 1078-0432

eISSN: 1557-3265

DOI: https://doi.org/10.1158/1078-0432.CCR-20-3679

Web address : https://doi.org/10.1158/1078-0432.CCR-20-3679

Abstract

Purpose: Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein that inhibits the tumor suppressor PP2A-B56 alpha. However, CIP2A mRNA variants remain uncharacterized. Here, we report the discovery of a CIP2A splicing variant, novel CIP2A variant (NOCIVA).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: NOCIVA contains CIP2A exons 1 to 13 fused to 349 nucleotides from CIP2A intron 13. Intriguingly, the first 39 nucleotides of the NOCIVA-specific sequence are in the coding frame with exon 13 of CIP2A 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 B56 alpha, but, whereas CIP2A is predominantly a cytoplasmic protein, NOCIVA translocates to the nucleus. Indicative of prevalent alternative splicing from CIP2A to NOCIVA in myeloid malignancies, AML and CML patient samples overexpress NOCIVA, but not CIP2A mRNA. In AML, a high NOCIVA/CIP2A mRNA expression ratio is a marker for adverse overall survival. In CML, high NOCIVA 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.