UC San Diego

The clinical course of Chronic Lymphocytic Leukemia (CLL) patients is heterogeneous: some patients progress relatively rapidly whereas others survive for many years without requiring therapy. Because static prognostic markers, such as IGVH mutation and ZAP-70 protein expression, lack indication of disease progression, alternative approaches for discriminating patients into their disparate risks for CLL progression is needed. By integrating gene expression measurements over sets of genes that encode proteins known to interact within a protein subnetwork we found 22 of the 38 significant subnetworks had increased activity in defined high-risk patients (referred to as pro-onconets) whereas the other 16 had decreased activity (referred to as anti-onconets). MicroRNA 181b (miR-181b) was described to decrease over time in patients with progressive CLL and not in those who remained indolent. Interestingly, one of the targets of miR-181b is SMAD2, a gene upregulated in the pro-onconets. With that said, miR-181b may regulate some pro-onconet pathways. In this study, we asked whether protein expression of our pro-onconet genes increased in protein expression over time and also if miR-181b may target SMAD2 transcript. Through western blot, quantitative Real-Time PCR, and transfection of miR-181b mimic into progressive CLL samples, we were able to answer these questions. This study shows that protein expression of these pro-onconet genes may increase over time and that miR-181b regulates SMAD2 expression. These studies value the importance of future studies investigating the oncogenic role of SMAD2, the relative expressions of target transcripts for particular microRNAs, and epigenetic regulation in progressive CLL