Active Chromatin Structure near MYB Occupancy at the Mir-155 Host Gene Promoter Coincides with Increased Mir-155 and MYB Levels In Chronic Lymphocytic Leukemia

Abstract 3589

Elevated levels of microRNA miR-155 represent a candidate pathogenic factor in chronic B-lymphocytic leukemia (B-CLL). In our study, B-CLL patients (N=71, F/M 31/40, median age 65) were subject to molecular analyses that found significant overexpression of MYB and miR-155 in B-CLL and physical association of MYB with the promoter of MIR155 host gene (MIR155HG, also known as B-cell integration cluster). In CD19+ B-cells derived from healthy control individuals (N=13), MYB and miR-155 expression was significantly lower. Next, we found that MYB positively regulates MIR155HG transcription in reporter assays. The endogenous chromatin structure of the MIR155HG promoter in B-CLL cells is characterized by spreading of active chromatin mark, histone H3K9 acetylation. Gene expression arrays on B-CLL patients (N=11) identified a set of predicted miR-155 target genes (N=94) that are downregulated. Their expression pattern displayed significant negative correlation with pri-miR-155 levels. Similarly, a number of MYB target genes were found deregulated (N=99) in B-CLL. Gene annotation of differentially expressed miR-155 and MYB targets in B-CLL revealed their biological functions as regulators of apoptosis (BCL2, API5), proliferation (CCND1, CCND2) and mediators of B-cell function (CD200, F11R). In addition, expression patterns of miR-155, MYB and their targets are currently being compared in a larger patient group with prognostic hallmarks of CLL (ZAP70, CD38, del(17)(p13.1), and IgVH). Our data collectively support novel candidate mechanism in B-CLL that includes MYB directly stimulating MIR155HG promoter coincident with its epigenetic dysregulation. (Grant # IGA 10310-3, MSMT 2B06077, 0021620806, LC06044, SVV-2010-254260507).