GENOME-WIDE PHARMACOLOGIC UNMASKING IDENTIFIES TUMOR SUPPRESSOR MICRORNAS IN MULTIPLE MYELOMA

Abstract

EPIGENETIC ALTERATIONS HAVE EMERGED AS AN IMPORTANT CAUSE OF MICRORNA (MIRNA) DEREGULATION. WE CONDUCTED GENOME-WIDE SCREENING FOR TUMOR SUPPRESSIVE MIRNAS EPIGENETICALLY SILENCED IN MM. FOUR HUMAN MM CELL LINES WERE TREATED WITH DEMETHYLATING AGENT 5?AZACYTIDINE (5?AZA). CONSISTENTLY UPREGULATED MIRNAS INCLUDE MIR-155, MIR-198, MIR-135A*, MIR-200C, MIR-125A-3P, MIR-188-5P, MIR-483-5P, MIR-663, AND MIR-630. METHYLATION ARRAY ANALYSIS REVEALED INCREASED METHYLATION AT OR NEAR MIRNA-ASSOCIATED CPG ISLANDS IN MM PATIENTS. ECTOPIC RESTORATION OF MIR-155, MIR-198, MIR-135A*, MIR-200C, MIR-663 AND MIR-483-5P SIGNIFICANTLY REPRESSED MM CELL PROLIFERATION, MIGRATION AND COLONY FORMATION. FURTHERMORE, WE DERIVED A 33-GENE SIGNATURE FROM PREDICTED MIRNA TARGET GENES THAT WERE ALSO UPREGULATED IN MM PATIENTS AND ASSOCIATED WITH PATIENT SURVIVAL IN THREE INDEPENDENT MYELOMA DATASETS. IN SUMMARY, WE HAVE REVEALED IMPORTANT, EPIGENETICALLY SILENCED TUMOR SUPPRESSIVE MIRNAS BY PHARMACOLOGIC REVERSAL