Show simple item record

dc.contributor.authorMakela, Eleonora
dc.contributor.authorPavic, Karolina
dc.contributor.authorVarila, Taru M
dc.contributor.authorSalmenniemi, Urpu
dc.contributor.authorLöyttyniemi, Eliisa
dc.contributor.authorNagelli, Srikar G
dc.contributor.authorAmmunét, Tea
dc.contributor.authorKähäri, Veli-Matti
dc.contributor.authorClark, Richard E
dc.contributor.authorElo, Laura L
dc.contributor.authorBachanaboyina, Venkata Kumari
dc.contributor.authorLucas, Claire M
dc.contributor.authorItälä-Remes, Maija
dc.contributor.authorWestermarck, Jukka
dc.date.accessioned2021-03-23T16:27:56Z
dc.date.available2021-03-23T16:27:56Z
dc.identifierhttps://chesterrep.openrepository.com/bitstream/handle/10034/624376/1078-0432.CCR-20-3679.full.pdf?sequence=1
dc.identifier.citationMakela, 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. https://doi.org/10.1158/1078-0432.CCR-20-3679en_US
dc.identifier.urihttp://hdl.handle.net/10034/624376
dc.descriptionThis 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-20-3679en_US
dc.description.abstractPurpose: 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.en_US
dc.publisherAmerican Association for Cancer Researchen_US
dc.relation.urlhttps://clincancerres.aacrjournals.org/content/early/2021/03/04/1078-0432.CCR-20-3679.longen_US
dc.rightsCC0 1.0 Universal*
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.subjectcip2aen_US
dc.subjectcmlen_US
dc.subjectamlen_US
dc.subjectNOCIVAen_US
dc.subjectLEUKAEMIAen_US
dc.titleDiscovery of a Novel CIP2A Variant (NOCIVA) with clinical relevance in predicting TKI resistance in myeloid leukemiasen_US
dc.typeArticleen_US
dc.identifier.eissn1557-3265en_US
dc.contributor.departmentUniversity of Turku; Åbo Akademi University; Helsinki University Hospital; Turku University Hospital; University of Liverpool; University of Chesteren_US
dc.identifier.journalClinical Cancer Researchen_US
or.grant.openaccessYesen_US
rioxxterms.funderUniversity of Turkuen_US
rioxxterms.identifier.projectIOM00019en_US
rioxxterms.versionAMen_US
rioxxterms.versionofrecord10.1158/1078-0432.CCR-20-3679en_US
rioxxterms.licenseref.startdate2022-03-05
dcterms.dateAccepted2021-03-02
rioxxterms.publicationdate2021-03-05
dc.date.deposited2021-03-23en_US
dc.indentifier.issn1078-0432en_US


Files in this item

Thumbnail
Name:
1078-0432.CCR-20-3679.full.pdf
Embargo:
2022-03-05
Size:
5.862Mb
Format:
PDF
Request:
Main article

This item appears in the following Collection(s)

Show simple item record

CC0 1.0 Universal
Except where otherwise noted, this item's license is described as CC0 1.0 Universal