Discovery of NOvel CIP2A VAriant (NOCIVA) and its clinical relevance in myeloid leukemias
| Autor: | Karolina Pavic, Eliisa Löyttyniemi, Maija Itälä-Remes, Venkata Kumari Bachanaboyina, Claire M. Lucas, Veli-Matti Kähäri, Urpu Salmenniemi, Taru Varila, Richard E. Clark, Jukka Westermarck, Srikar G. Nagelli, Eleonora Makela |
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| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
Myeloid Alternative splicing Intron Myeloid leukemia Imatinib Biology 3. Good health Dasatinib 03 medical and health sciences Exon 0302 clinical medicine medicine.anatomical_structure 030220 oncology & carcinogenesis RNA splicing Cancer research medicine 030304 developmental biology medicine.drug |
| Popis: | Cancerous inhibitor of PP2A (CIP2A) is a prevalent human oncoprotein that inhibits tumor suppressor PP2A-B56a. However, CIP2A mRNA and protein variants remain uncharacterized. Here, we report discovery of a CIP2A splicing variant NOCIVA (NOvel CIp2a VAriant). NOCIVA contains CIP2A exons 1-13 fused to a continuous stretch of 349 nucleotide from CIP2A intron 13. Intriguingly, the first 39 nucleotides of the NOCIVA specific sequence are in coding frame with exon 13 of CIP2A, and codes for a 13 amino acid peptide tail unhomologous 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 nucleus. Indicative of prevalent alternative splicing from CIP2A to NOCIVA in myeloid malignancies, acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) patient samples overexpress NOCIVA, but not CIP2A mRNA. In AML, high NOCIVA mRNA expression is a marker for adverse overall survival. In CML, high NOCIVA expression associates with inferior event free survival among imatinib treated patients, but not among patients treated with dasatinib or nilotinib. Collectively, we describe discovery of a novel variant of oncoprotein CIP2A, and its clinical relevance in myeloid leukemias.Key PointsDiscovery and characterization of a first mRNA variant of one of the most prevalently deregulated human oncoproteins CIP2AUnlike CIP2A, NOCIVA mRNA is overexpressed in AML and CML patient samples and associates with poor clinical response in both myeloid cancers |
| Databáze: | OpenAIRE |
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