Epigenetic inactivation of the miR-34a in hematological malignancies

Abstract

BACKGROUND : miR-34a is a transcriptional target of p53, and implicated in carcinogenesis. AIM: We studied the role of miR-34a methylation in a panel of hematological malignancies including acute leukemia (AML, ALL), chronic leukemia (CLL and CML), multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). METHODS: The methylation status of miR-34a promoter was studied in 12 cell lines and 188 diagnostic samples by methylation-specific PCR. RESULTS: miR-34a promoter was unmethylated in normal controls but methylated in 75% lymphoma and 37% myeloma cell lines. Hypomethylating treatment led to re-expression of pri-miR-34a transcript in lymphoma cells with homozygous miR-34a methylation. In primary samples at diagnosis, miR-34a methylation was detected in 4% CLL, 5.5% MM samples, and 18.8% of NHL at diagnosis but none of ALL, AML and CML (p=0.011). In MM patients with paired samples, miR-34a methylation status remained unchanged at progression. Amongst lymphoid malignancies, miR-34a was preferentially methylated in NHL (p=0.018), in particular natural killer/T cell (NK/T cell) lymphoma. SUMMARY: Amongst hematological malignancies, miR-34a methylation is preferentially hypermethylated in NHL, in particular NK/T cell lymphoma, in a tumor-specific manner, therefore the role of miR-34a in lymphomagenesis warrants further study.