Uncovering the Role of RNA-Binding Protein hnRNP K in B-Cell Lymphomas
| Autor: | Xiaorui Zhang, Todd M. Link, Vrutant Shah, Laura R. Pageon, Carlos E. Bueso-Ramos, Meng Han Wu, Sean M. Post, Huaxian Ma, Sanzhar Alybayev, Marisa J.L. Aitken, Miguel Gallardo, Joaquin Martinez-Lopez, Ken H. Young, Rodrigo Jacamo, Prerna Malaney, Li Yu, Dos D. Sarbassov, Inmaculada Rapado, Zijun Y. Xu-Monette, Michelle Craig Barton, Haley Steinman, Hun Ju Lee |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Adult
Male Genetically modified mouse Cancer Research Lymphoma B-Cell Transgene Gene Expression Antineoplastic Agents Mice Transgenic Context (language use) Biology environment and public health Heterogeneous-Nuclear Ribonucleoprotein K Mice 03 medical and health sciences 0302 clinical medicine Cell Line Tumor medicine Animals Humans Protein Interaction Domains and Motifs B cell Aged Neoplasm Staging 030304 developmental biology 0303 health sciences Oncogene RNA-Binding Proteins Articles Middle Aged medicine.disease Lymphoma Gene Expression Regulation Neoplastic Transplantation Disease Models Animal Phenotype medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Cancer research Female Lymphoma Large B-Cell Diffuse Disease Susceptibility Diffuse large B-cell lymphoma Protein Binding |
| Zdroj: | J Natl Cancer Inst |
| ISSN: | 1460-2105 0027-8874 |
| DOI: | 10.1093/jnci/djz078 |
| Popis: | Background Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is an RNA-binding protein that is aberrantly expressed in cancers. We and others have previously shown that reduced hnRNP K expression downmodulates tumor-suppressive programs. However, overexpression of hnRNP K is the more commonly observed clinical phenomenon, yet its functional consequences and clinical significance remain unknown. Methods Clinical implications of hnRNP K overexpression were examined through immunohistochemistry on samples from patients with diffuse large B-cell lymphoma who did not harbor MYC alterations (n = 75). A novel transgenic mouse model that overexpresses hnRNP K specifically in B cells was generated to directly examine the role of hnRNP K overexpression in mice (three transgenic lines). Molecular consequences of hnRNP K overexpression were determined through proteomics, formaldehyde-RNA-immunoprecipitation sequencing, and biochemical assays. Therapeutic response to BET-bromodomain inhibition in the context of hnRNP K overexpression was evaluated in vitro and in vivo (n = 3 per group). All statistical tests were two-sided. Results hnRNP K is overexpressed in diffuse large B-cell lymphoma patients without MYC genomic alterations. This overexpression is associated with dismal overall survival and progression-free survival (P Conclusion Our findings indicate that hnRNP K is a bona fide oncogene when overexpressed and represents a novel mechanism for c-Myc activation in the absence of MYC lesions. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|