Targeting Bruton's tyrosine kinase expression levels through microRNAs in chronic lymphocytic leukemia treatment

CLL is the most common leukemia in the western world and is characterized by the accumulation of monoclonal mature circulating CD5+ B cells that generally express low levels of surface immunoglobulin (Ig). Many lines of evidence indicate that chronic signaling through the B-cell receptor (BCR) plays a key role in CLL pathogenesis. CLL prognosis is correlated with the BCR somatic hypermutation status and the CLL BCR repertoire is highly restricted. Often, CLL cells show constitutive activation of several kinases that are activated immediately downstream of the BCR. Thus, the BCR signaling pathway is aberrantly active in CLL and may play a role in disease development. One of the signal transduction molecules downstream of the BCR is BTK, a Tec family non-receptor kinase that is primarily expressed in most hematopoietic lineages, but not in T cells. BTK has been shown to be essential for several constitutively active pathways implicated in CLL cell survival, including the AKT, ERK and NF-κB pathway. Importantly, small molecule inhibitors of BTK have shown impressive anti-tumor activity in clinical studies, with high response rates in various B cell malignancies, in particular CLL. [...]