Department of Leukemia.
H12O-CNIO Haematological Malignancies Clinical Research Unit, Clinical Research Programme, CNIO, Madrid, Spain.
J Natl Cancer Inst. 2020 Jan 1;112(1):95-106. doi: 10.1093/jnci/djz078.
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.
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.
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 < .001). Overexpression of hnRNP K 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 hnRNP K'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 hnRNP K-mediated c-Myc activation in patients.
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.
异质核核糖核蛋白 K（hnRNP K）是一种 RNA 结合蛋白，在癌症中异常表达。我们和其他人之前已经表明，hnRNP K 表达的减少会下调肿瘤抑制程序。然而，hnRNP K 的过表达是更常见的临床现象，但其功能后果和临床意义仍然未知。
通过对未携带 MYC 改变的弥漫性大 B 细胞淋巴瘤患者的样本进行免疫组织化学检查，研究 hnRNP K 过表达的临床意义（n=75）。生成了一种新型的转基因小鼠模型，该模型特异性地在 B 细胞中过表达 hnRNP K，以直接研究 hnRNP K 过表达在小鼠中的作用（三个转基因系）。通过蛋白质组学、甲醛 RNA 免疫沉淀测序和生化测定确定 hnRNP K 过表达的分子后果。在体外和体内评估 BET 溴结构域抑制在 hnRNP K 过表达背景下的治疗反应（每组 3 个）。所有统计检验均为双侧。
hnRNP K 在没有 MYC 基因组改变的弥漫性大 B 细胞淋巴瘤患者中过表达。这种过表达与总体生存率和无进展生存率降低相关（P<.001）。在转基因小鼠中过表达 hnRNP K 导致淋巴瘤的发生和生存率降低（所有转基因系均 P<.001；Line 171[n=30]：危险比[HR]=64.23，95%置信区间[CI]=26.1 至 158.0；Line 173[n=31]：HR=25.27，95%CI=10.3 至 62.1；Line 177[n=25]：HR=119.5，95%CI=42.7 至 334.2，与野生型小鼠相比）。临床样本、小鼠模型、全筛选测定和生化研究表明，hnRNP K 的致癌潜能源于其在转录后和翻译水平上调节 MYC 的能力。因此，在体外和移植模型中，Hnrnpk 的过表达使细胞对 BET 溴结构域抑制敏感，这代表了一种减轻患者中 hnRNP K 介导的 c-Myc 激活的策略。
我们的研究结果表明，hnRNP K 在过表达时是一种真正的癌基因，代表了在没有 MYC 病变的情况下 c-Myc 激活的新机制。
