A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Discovery of a Novel CIP2A Variant (NOCIVA) with Clinical Relevance in Predicting TKI Resistance in Myeloid Leukemias
Tekijät: 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
Kustantaja: AMER ASSOC CANCER RESEARCH
Julkaisuvuosi: 2021
Journal: Clinical Cancer Research
Lehden akronyymi: CLIN CANCER RES
Vuosikerta: 27
Numero: 10
Aloitussivu: 2848
Lopetussivu: 2860
Sivujen määrä: 13
ISSN: 1078-0432
eISSN: 1557-3265
DOI: https://doi.org/10.1158/1078-0432.CCR-20-3679
Verkko-osoite: https://doi.org/10.1158/1078-0432.CCR-20-3679
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.
