Discovery of a Novel CIP2A Variant (NOCIVA) with clinical relevance in predicting TKI resistance in myeloid leukemias
Authors
Makela, EleonoraPavic, Karolina
Varila, Taru M.
Salmenniemi, Urpu
Löyttyniemi, Eliisa
Nagelli, Srikar G.
Ammunét, Tea
Kähäri, Veli-Matti
Clark, Richard E.
Elo, Laura L.
Bachanaboyina, Venkata Kumari
Lucas, Claire
Itälä-Remes, Maija
Westermarck, Jukka
Affiliation
University of Turku; Åbo Akademi University; Helsinki University Hospital; Turku University Hospital; University of Liverpool; University of Chester
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Purpose: Cancerous inhibitor of PP2A (CIP2A) is an oncoprotein that inhibits the tumor suppressor PP2A-B56a. However, CIP2A mRNA variants remain uncharacterized. Here, we report the discovery of a CIP2Asplicing variant, NOCIVA (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: NOCIVA contains CIP2A exons 1-13 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 B56a, 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 novel variant of the oncoprotein CIP2A and its clinical relevance in predicting tyrosine kinase inhibitor therapy resistance in myeloid leukemias.Citation
Makela, E., Pavic, K., Varila, T. M., Salmenniemi, U., Löyttyniemi, E., Nagelli, S. G., . . . Westermarck, J. (2021). Discovery of a Novel CIP2A variant (NOCIVA) with clinical relevance in predicting TKI resistance in myeloid leukemias. Clinical Cancer Research, 27(10), 2848–2860. https://doi.org/10.1158/1078-0432.CCR-20-3679Publisher
American Association for Cancer ResearchJournal
Clinical Cancer ResearchAdditional Links
https://clincancerres.aacrjournals.org/content/early/2021/03/04/1078-0432.CCR-20-3679.longType
ArticleDescription
This document is the Accepted Manuscript version of a published work that appeared in final form in [Clinical Cancer Research]. To access the final edited and published work see http://dx.doi.org/10.1158/1078-0432.CCR-20-3679ISSN
1078-0432EISSN
1557-3265ae974a485f413a2113503eed53cd6c53
10.1158/1078-0432.CCR-20-3679
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