MYC Causes Multiple Myeloma Progression via Attenuating TP53-Induced MicroRNA-34 Expression.

MicroRNAs (miRNAs and miRs) are small (19-25 base pairs) non-coding RNAs with the ability to modulate gene expression. Previously, we showed that the miR-34 family is downregulated in multiple myeloma (MM) as the cancer progressed. In this study, we aimed to clarify the mechanism of miRNA dysregulation in MM. We focused particularly on the interaction between MYC and the TP53-miR34 axis because there is a discrepancy between increased TP53 and decreased miR-34 expressions in MM. Using the nutlin-3 or Tet-on systems, we caused wild-type (WT) p53 protein accumulation in human MM cell lines (HMCLs) and observed upregulated miR-34 expression. Next, we found that treatment with an Myc inhibitor alone did not affect miR-34 expression levels, but when it was coupled with p53 accumulation, miR-34 expression increased. In contrast, forced MYC activation by the MYC-ER system reduced nutlin-3-induced miR-34 expression. We also observed that TP53 and MYC were negatively correlated with mature miR-34 expressions in the plasma cells of patients with MM. Our results suggest that MYC participates in the suppression of p53-dependent miRNA expressions. Because miRNA expression suppresses tumors, its inhibition leads to MM development and malignant transformation.

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

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.

Integrin α7 and Extracellular Matrix Laminin 211 Interaction Promotes Proliferation of Acute Myeloid Leukemia Cells and Is Associated with Granulocytic Sarcoma.

Acute myeloid leukemia (AML) with granulocytic sarcoma (GS) is characterized by poor prognosis; however, its underlying mechanism is unclear. Bone marrow samples from 64 AML patients (9 with GS and 55 without GS) together with AML cell lines PL21, THP1, HL60, Kasumi-1, and KG-1 were used to elucidate the pathology of AML with GS. RNA-Seq analyses were performed on samples from seven AML patients with or without GS. Gene set enrichment analyses revealed significantly upregulated candidates on the cell surface of the GS group. Expression of the adhesion integrin α7 (ITGA7) was significantly higher in the GS group, as seen by RT-qPCR (p = 0.00188) and immunohistochemistry of bone marrow formalin-fixed, paraffin-embedded (FFPE) specimens. Flow cytometry revealed enhanced proliferation of PL21 and THP1 cells containing surface ITGA7 in the presence of laminin 211 and stimulated ERK phosphorylation; this effect was abrogated following ITGA7 knockdown or ERK inhibition. Overall, high ITGA7 expression was associated with poor patient survival (p = 0.0477). In summary, ITGA7 is highly expressed in AML with GS, and its ligand (laminin 211) stimulates cell proliferation through ERK signaling. This is the first study demonstrating the role of integrin α7 and extracellular matrix interactions in AML cell proliferation and extramedullary disease development.

The Role and Function of microRNA in the Pathogenesis of Multiple Myeloma.

Recently, attention has been drawn to the role of non-coding regions of the genome in cancer pathogenesis. MicroRNAs (miRNAs) are small non-coding RNAs with 19-25 bases of length that control gene expression by destroying messenger RNA or inhibiting its translation. In multiple myeloma (MM), the expression of several miRNAs, such as miR-15a and miR-16, is markedly decreased and their target genes upregulated, suggesting their role as tumor-suppressing miRNAs. In contrast, miRNAs such as miR-21 and miR-221 are highly expressed and function as oncogenes (oncomiRs). In addition, several miRNAs, such as those belonging to the miR-34 family, are transcriptional targets of p53 and mediate its tumor-suppressive functions. Many miRNAs are associated with drug resistance, and the modulation of their expression or activity might be explored to reverse it. Moreover, miRNA expression patterns in either MM cells or serum exosomes have been shown to be good prognostic markers. miRNA regulation mechanisms have not been fully elucidated. Many miRNAs are epigenetically controlled by DNA methylation and histone modification, and others regulate the expression of epigenetic modifiers, indicating that miRNA and other epigenetic effectors are part of a network. In this review, we outlined the roles of miRNAs in MM and their potential to predict MM prognosis and develop novel therapies.