MiR-155/miR-150 network regulates progression through the disease phases of chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a slowly developing progression-prone disease. MicroRNAs miR-155 and miR-150 are small inhibitors of gene expression in B-cells that were previously connected to the pathogenesis of CLL. We herein evaluated relationship of miR-155/miR-150 network with clinical and routine laboratory parameters of the CLL patient cohort utilizing multivariate analyses and found its association with overall survival and progression of CLL. Aggressive course in CLL affects ~ 20–40% patients as indicated by the clonal-evolution data. One of the strongest aggressive course associates is 17p13 deletion occurring in 5–10% of CLL patients. Other risk associates were previously connected with the B-cell receptor signaling, including the CD38, ZAP-70, and intact variable region of IgH (IgHV). Recently, miR-155 has been connected with CLL aggressiveness and progression of the monoclonal B-cell lymphocytosis (MBL). Our group suggested that it is the transcriptional upregulation of the miR-155 host gene (MIR155HG) via the Myeloblastoma proto-oncogene (MYB) that lead to the increased level of the mature miR-155 in CLL, which may represent the molecular pathway of CLL aggressiveness. In addition, the downstream events of miR-155 overexpression, including downregulation of transcription factor PU.1 may also coincide with CLL aggressiveness and patient outcome. Another miR-155 target is the Src homology-2 domain-containing inositol 5-phosphatase 1 (SHIP1), which supposedly blocks the B-cell receptor signaling (BCR). Indeed, treating the CLL or normal B-cells with the CD40-ligand or the B-cell-activating factor upregulated the miR-155 level and enhanced sensitivity to the BCR ligation, effects that could be blocked by inhibitors of miR-155. Furthermore, another microRNA involved in the B-cell differentiation, miR-150, has also been shown to interfere with the BCR signaling by additional mechanisms involving its targets GAB1 and FOXP1 and presumably also through its betterrecognized target MYB. Such possibility was also supported elsewhere. Importantly, while the miR-155 and the miR-150 targets (such as MYB) are rather negative CLL predictors, the levels of miR-150 and the miR-155 targets (SHIP1, PU.1) could be considered as the positive predictors, although the complete network has not been tested yet. Both miR-155 and miR-150 were validated as the crucial components regulating sensitivity to the BCR ligation in CLL. We herein investigated how levels of miR-155, miR-150 and their network associate with clinical outcome of 127 CLL patients (36 females and 91 males, age range 36–88; median age 65,