Uncovering the Role of RNA-Binding Protein hnRNP K in B-Cell Lymphomas.

Abstract

Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is an RNA-binding protein that is aberrantly expressed in cancers. We and others have previously shown that reduced hnRNPK expression downmodulates tumor-suppressive programs. However, overexpression of hnRNPK is the more commonly observed clinical phenomenon, yet its functional consequences and clinical significance remain unknown. Clinical implications of hnRNPK 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 hnRNPK specifically in B cells was generated to directly examine the role of hnRNPK overexpression in mice (three transgenic lines). Molecular consequences of hnRNPK overexpression were determined through proteomics, formaldehyde-RNA-immunoprecipitation sequencing, and biochemical assays. Therapeutic response to BET-bromodomain inhibition in the context of hnRNPK overexpression was evaluated in vitro and in vivo (n = 3 per group). All statistical tests were two-sided. hnRNPK 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 < .001). Overexpression of hnRNPK in transgenic mice resulted in the development of lymphomas and reduced survival (P < .001 for all transgenic lines; Line 171[n = 30]: hazard ratio [HR] = 64.23, 95% confidence interval [CI] = 26.1 to 158.0; Line 173 [n = 31]: HR = 25.27, 95% CI = 10.3 to 62.1; Line 177 [n = 25]: HR = 119.5, 95% CI = 42.7 to 334.2, compared with wild-type mice). Clinical samples, mouse models, global screening assays, and biochemical studies revealed that hnRNPK's oncogenic potential stems from its ability to posttranscriptionally and translationally regulate MYC. Consequently, Hnrnpk overexpression renders cells sensitive to BET-bromodomain-inhibition in both in vitro and transplantation models, which represents a strategy for mitigating hnRNPK-mediated c-Myc activation in patients. Our findings indicate that hnRNPK is a bona fide oncogene when overexpressed and represents a novel mechanism for c-Myc activation in the absence of MYC lesions.