Uncovering the role of hnRNP K, an RNA-binding protein, in B-cell lymphomas.
BACKGROUND: 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 (DLBCL) 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 DLBCL patients without MYC genomic alterations. This overexpression is associated with dismal OS and PFS (p < 0.001). Overexpression of hnRNP K in transgenic mice resulted in the development of lymphomas and reduced survival (p < 0.001 for all transgenic lines; Line 171 (n = 30): HR = 64.23, 95% CI = 26.1-158.0; Line 173 (n = 31): HR = 25.27, 95% CI = 10.3-62.1; Line 177 (n = 25): HR = 119.5, 95% CI = 42.7-334.2, compared to wild-type mice). Clinical samples, mouse models, global screening assays, and biochemical studies revealed that hnRNP K's oncogenic potential stems from its ability to post-transcriptionally and translationally regulate MYC. Consequently, Hnrnpk overexpression renders cells sensitive to BET-bromodomain-inhibition in in vitro and transplantation models, which represents a strategy for mitigating hnRNP K-mediated c-Myc activation in patients. 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.
Gallardo, M; Malaney, P; Aitken, MJL; Zhang, X; Link, TM; Shah, V; Alybayev, S; Wu, M-H; Pageon, LR; Ma, H; Jacamo, R; Yu, L; Xu-Monette, ZY; Steinman, H; Lee, HJ; Sarbassov, D; Rapado, I; Barton, MC; Martinez-Lopez, J; Bueso-Ramos, C; Young, KH; Post, SM
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