Epigenetic Inactivation of the miR-124-1 in Haematological Malignancies

Abstract

miR-124-1 is a tumour suppressor microRNA (miR). Epigenetic deregulation of miRs is implicated in carcinogenesis. Promoter DNA methylation and histone modification of miR-124-1 was studied in 5 normal marrow controls, 4 lymphoma, 8 multiple myeloma (MM) cell lines, 230 diagnostic primary samples of acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), chronic myeloid leukaemia (CML), chronic lymphocytic leukaemia (CLL), MM, and non-Hodgkin's lymphoma (NHL), and 53 MM samples at stable disease or relapse. Promoter of miR-124-1 was unmethylated in normal controls but homozygously methylated in 4 of 4 lymphoma and 4 of 8 myeloma cell lines. Treatment of 5-Aza-2′-deoxycytidine led to miR-124-1 demethylation and re-expression of mature miR-124, which also associated with emergence of euchromatic trimethyl H3K4 and consequent downregulation of CDK6 in myeloma cells harboring homozygous miR-124-1 methylation. In primary samples at diagnosis, miR-124-1 methylation was absent in CML but detected in 2% each of MM at diagnosis and relapse/progression, 5% ALL, 15% AML, 14% CLL and 58.1% of NHL (p<0.001). Amongst lymphoid malignancies, miR-124-1 was preferentially methylated in NHL than MM, CLL or ALL. In primary lymphoma samples, miR-124-1 was preferentially hypermethylated in B- or NK/T-cell lymphomas and associated with reduced miR-124 expression. In conclusion, miR-124-1 was hypermethylated in a tumour-specific manner, with a heterochromatic histone configuration. Hypomethylation led to partial restoration of euchromatic histone code and miR re-expression. Infrequent miR-124-1 methylation detected in diagnostic and relapse MM samples showed an unimportant role in MM pathogenesis, despite frequent methylation found in cell lines. Amongst haematological cancers, miR-124-1 was more frequently hypermethylated in NHL, and hence warrants further study.

Constitutive activation of Pim1 kinase is a therapeutic target for adult T-cell leukemia

“…miR-223 and miR-150 have been shown to regulate STAT1 activity 28 ; miR-31 mediates NF-kB-inducing kinase activity in HTLV-I cells, 29 whereas miR-28-3p regulates HTLV-I viral replication. 30 A tumor suppressor effect for miR-124a has been suggested for some cancers, [31][32][33] but to date, miR-124a had not been studied in ATL. Our data demonstrate that miR-124a is a potent tumor suppressor in ATL by targeting the STAT3-Pim1 axis.…”

Mechanisms of epigenetic deregulation in lymphoid neoplasms

“…106 DNA hypermethylation led to miR-124 and miR-203 silencing in several lymphoid malignancies, providing a basis for therapeutic targeting with demethylating agents. [107][108][109][110][111][112] Moreover, genome-wide miRNA profiling studies in ALL further revealed an EZH2 targeted and aberrantly methylated miRNA signature, suggesting that these cases might benefit from EZH2 inhibition. [107][108][109][110][111]113 Along the same lines, miR-26a and miR-29 are repressed by MYC during lymphomagenesis.…”

The role of miRNAs in the pathogenesis and diagnosis of B-cell lymphomas

“…DNA hypermethylation is responsible for the decrease of miRNA in NHL. It is the case of loss of expression of miR-124a 113 and miR-203 114 in a variety of hematologic malignancies, of miR-9 in some BL cases, 115 and of miR-139 and miR-582 (among others) in CLL. 116 In addition, conventional transcription factors can also regulate miRNA expression.…”