Long Noncoding RNA PVT1 Is Regulated by Bromodomain Protein BRD4 in Multiple Myeloma and Is Associated with Disease Progression.

Hiroshi Handa,Ken-Ichi Tahara,Yuta Masuda,Yuko Kuroda,Yuki Murakami,Nobuhiko Kobayashi,Tetsuhiro Kasamatsu,Hirokazu Murakami,Takayuki Saitoh,Kei Kimura-Masuda,Hisashi Takei,Kazuki Honma,Rei Ishihara,Saki Watanabe,Tsukasa Oda

doi:10.3390/ijms21197121

Abstract

Long noncoding RNAs (lncRNAs) are deregulated in human cancers and are associated with disease progression. Plasmacytoma Variant Translocation 1 (PVT1), a lncRNA, is located adjacent to the gene MYC, which has been linked to multiple myeloma (MM). PVT1 is expressed in MM and is associated with carcinogenesis. However, its role and regulation remain uncertain. We examined PVT1/MYC expression using real-time PCR in plasma cells purified from 59 monoclonal gammopathy of undetermined significance (MGUS) and 140 MM patients. The MM cell lines KMS11, KMS12PE, OPM2, and RPMI8226 were treated with JQ1, an MYC super-enhancer inhibitor, or MYC inhibitor 10058-F4. The expression levels of PVT1 and MYC were significantly higher in MM than in MGUS (p < 0.0001) and were positively correlated with disease progression (r = 0.394, p < 0.0001). JQ1 inhibited cell proliferation and decreased the expression levels of MYC and PVT1. However, 10054-F4 did not alter the expression level of PVT1. The positive correlation between MYC and PVT1 in patients, the synchronous downregulation of MYC and PVT1 by JQ1, and the lack of effect of the MYC inhibitor on PVT1 expression suggest that the expression of these two genes is co-regulated by a super-enhancer. Cooperative effects between these two genes may contribute to MM pathogenesis and progression.

Highlights

Multiple myeloma (MM) is a plasma cell neoplasm characterized by the proliferation of atypical plasma cells in the bone marrow and the production of monoclonal immunoglobulins
Plasmacytoma Variant Translocation 1 (PVT1) expression seemed to increase with disease progression, but it did not differ between samples from different stages (stages are defined according to the international staging system (ISS) reflecting progression) (p = 0.145, Figure 1C)
Since PVT1 is located on chromosome 8q24 and co-occurrence of 8q24 abnormality is sometimes observed in MM, we compared the expression levels between cell lines with 8q24 abnormalities, including

Summary

Introduction

Multiple myeloma (MM) is a plasma cell neoplasm characterized by the proliferation of atypical plasma cells in the bone marrow and the production of monoclonal immunoglobulins. The primary molecular mechanism of MM development is thought to be the activation of cancer-related genes by translocations of immunoglobulin heavy chain genes (IgH). The effects of these translocations include increased cyclin D1 expression by the translocation t(11; 14) IgH-CCND1, increased FGFR3/MMSET expression by t(4; 14) IgH-FGFR3/MMSET, and increased c-MAF expression by t(14; 16) IgH-c-MAF [4]. These chromosomal abnormalities are observed at the MGUS stage, so additional abnormalities are required for progression to MM.

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