Epigenetic inactivation of the MIR34B/C in multiple myeloma

Abstract

We postulated that MIR34B/C, a direct transcriptional target of TP53, might be inactivated by promoter hypermethylation in multiple myeloma (MM). MIR34B/C promoter methylation was studied in 8 normal marrow controls, 8 MM cell lines, 95 diagnostic, and 23 relapsed/progressed MM samples by methylation-specific PCR. MIR34B/C was methylated in 6 (75.0%) MM cell lines but not normal controls. 5-Aza-2'-deoxycytidine led to MIR34B/C promoter demethylation and MIR34B reexpression. Moreover, restoration of MIR34B led to reduced cellular proliferation and enhanced apoptosis of myeloma cells. In primary samples, methylation of MIR34B/C occurred in 5.3% at diagnosis and 52.2% at relapse/disease progression (P < .001). In 12 MM patients with paired samples at diagnosis and relapse/progression, MIR34B/C methylation was acquired in 6 at relapse/progression. In conclusion, MIR34B/C is a tumor suppressor in myeloma. Hypermethylation of MIR34B/C is tumor-specific. Frequent MIR34B/C hypermethylation during relapse/progression but not at diagnosis implicated a role of MIR34B/C hypermethylation in myeloma relapse/progression.

piRNA-823 contributes to tumorigenesis by regulating de novo DNA methylation and angiogenesis in multiple myeloma

“…10,11 Nowadays, the relevance of ncRNAs to MM has mainly focused on microRNAs (miRNAs) expression and function. Although growing evidence supports a role for miRNAs as targets of DNA hypermethylation in MM, [12][13][14] the role for miRNAs as effectors to govern DNA methylation to regulate methylation-dependent TSGs expression has not been fully explored. Recently, a distinct class of small ncRNAs, called Piwi-interacting RNAs (piRNAs), which has been discovered to be implicated in regulating de novo DNA methylation, [15][16][17] has caused great concern.…”

Epigenetic inactivation ofDAPK1,p14ARF,mir-34aand-34b/cin acute promyelocytic leukaemia

“…miR-34b and - 34c are an miRNA cluster localised to chromosome 11q23, sharing the same primary transcript 25. Overexpression of miR-34b in myeloma cell line results in enhanced cell death and inhibition of cell proliferation, thereby demonstrating its tumour suppressor property 26. In addition, frequent hypermethylation of miR-34b/c has been reported in multiple myelomas 26…”

Whole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers

“…Hypermethylation of RASD1, for example, has been correlated with resistance of MM to dexamethasone (Nojima et al 2009). Inappropriate DNA methylation of TNFRSF18 (also known as GITR) (Liu et al 2013), MIR34B/C (Wong et al 2011), or the combined inactivation of genes GPX3, RBP1, SPARC, and TGFBI (Kaiser et al 2013) have been associated with poor prognosis, survival, and disease progression in patients with MM.…”