Upregulation of SOCS-1 and Downregulation of miR-214 Correlate with Disease Course in Chronic Lymphocytic Leukemia.

SOCS-1, suppressor of cytokine signaling, is a negative regulator of the JAK2/STAT signal transduction pathway. This pathway, often deregulated in myeloproliferative disorders, has not yet been implicated in chronic lymphocytic leukemia (CLL). We demonstrated SOCS-1 upregulation and miR-214 downregulation with clinical response in a patient treated with cladribine. Similar changes were not seen in a treated patient with progressive disease. MicroRNAs (miRNAs) are a class of small non-coding RNAs that regulate expression of other genes by complementary pairing at the seed sequence in the 3′-UTR of the target mRNA. Some patients with CLL reportedly regulate bcl-2 expression by downregulating miR-15a and miR-16-1. Although no experimentally verified targets have been demonstrated for miR-214, complete inhibition of miR-214 by anti-sense inhibitors prevents apoptosis in Hela cells. Of the 44 predicted human miRNAs that target SOCS-1 (http://microrna.sanger.ac.uk), we determined the expression of 24 of these by real-time PCR using the Early Access Human Panel from Applied Biosystems. MiR-214 was the only downregulated miRNA after treatment. The other 23 miRNAs were either upregulated or unchanged. We demonstrated SOCS-1 protein upregulation by two fold after cladribine in the “responsive” patient without a concomitant increase in the transcript level as measured by real time PCR. SOCS-1 expression is often silenced by DNA promoter methylation in hematologic and solid tumor malignancies. We report another mechanism of regulation through miRNA translational repression. This suggests involvement of the JAK2/STAT pathway in B-cell survival in CLL.