Abstract
Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by rapid disease progression. The needs for new therapeutic strategies for MCL patients call for further understanding on the molecular mechanisms of pathogenesis of MCL. Recently, long noncoding RNAs (lncRNAs) have been recognized as key regulators of gene expression and disease development, however, the role of lncRNAs in non-Hodgkin lymphoma and specifically in MCL is still unknown. Next generation RNA-sequencing was carried out on MCL patient samples along with normal controls and data was analyzed. As a result, several novel lncRNAs were found significantly overexpressed in the MCL samples with lncRNA ROR1-AS1 the most significant one. We cloned the ROR1-AS1 lncRNA in expression vector and ectopically transfected in MCL cell lines. Results showed that overexpression of ROR1-AS1 lncRNA promoted growth of MCL cells while decreased sensitivity to the treatment with drugs ibrutinib and dexamethasone. ROR-AS1 overexpression also decreased the mRNA expression of P16 (P = 0.21), and SOX11 (p = 0.017), without much effect on P53, ATM and P14 mRNA. RNA-immunoprecipitation assays demonstrated high affinity binding of lncRNA ROR1-AS1 with EZH2 and SUZ12 proteins of the polycomb repressive complex-2 (PRC2). Suppressing EZH2 activity with pharmacological inhibitor GSK343 abolished binding of ROR1-AS1 with EZH2. Taken together, this study identified a functional lncRNA ROR-AS1 involved with regulation of gene transcription via associating with PRC2 complex, and may serve as a novel biomarker in MCL patients.
Highlights
Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy usually diagnosed as a late-stage disease with patients above 60 years old
For sorted Long noncoding RNAs (lncRNAs), we used log2 fold changes greater than 10 and p-value less than 0.05. Based on these criteria we identified ten different lncRNAs upregulated in MCL patient samples with ROR1-AS1 on the top of the list (Figure 1A)
Our analysis further showed that lncRNA ROR1-AS1 is predominantly localized in the nucleus, and physically associates with core proteins of polycomb repressive complex-2 (PRC2) complex such as EZH2 and SUZ12
Summary
Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy usually diagnosed as a late-stage disease with patients above 60 years old. The median survival of MCL patients has increased with the development of new therapeutic strategies [1, 2], MCL has been regarded as an incurable blood cancer that is characterized by rapid disease progression. The transcription factor SOX11 has been identified as a specific marker for both Cyclin D1 positive and negative MCL and regarded as a key gene in the pathogenesis of MCL [8, 9]. Some of the key biological processes regulated through lncRNAs include epigenetic and transcriptional regulation of gene expression [11, 12], post-transcriptional regulation such as mRNA processing, and translation [1318], cell differentiation and development [19] and human disease especially the cancer [20]. We aimed to identify the lncRNAs deregulated in MCL and explore their role in MCL pathogenesis
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