Schema to show transcription, translation, and posttranslation modifications that lead to production and maintenance of Mcl-1 proteins in normal and/or malignant B cells and therapeutic strategies (shown in red rectangles and red text) to interfere with these processes. Signals from microenvironment, growth factors, and cytokines are shown in black dashed lines as they result in increased expression of transcription factors and survival factors in CLL cells. Small molecule agents that interfere with microenvironment and CLL cell interactions reduce survival signals. Myc-driven transcription could be inhibited by Pim kinase inhibitors. The adenylate/uridylate-rich elements in the 3' untranslated region of Mcl-1 transcripts target them for rapid degradation. Global transcription inhibitors, such as flavopiridol or polyadenylation inhibitors, work to reduce Mcl-1 transcripts due to their fast turnover. Pharmacologic agents that shut down protein synthesis result in lower Mcl-1 protein levels due to the short half-life of this protein. Phosphorylation of Mcl-1 on Ser159 by activated GSK3β (unphosphorylated form) results in faster degradation of Mcl-1 through proteasomal pathway. However, GSK3β could be phosphorylated and inactivated by Akt. Hence, Akt inhibition is a therapeutic strategy. Mcl-1 sequesters proapoptotic proteins, and the latter could be released by use of BH3 mimetics, leading to cell death and Mcl-1 degradation. Similarly, chemotherapeutic agents activate caspases that could cleave Mcl-1. Mcl-1 is phosphorylated on Ser64 by Erk, resulting in stabilization of Mcl-1 protein and cell survival. Inset shows the structure of Mcl-1 protein with BH1, 2, and 3 domains, transmembrane domain, and PEST sequences where caspase cleavage sites are located. Some of these pathways are recognized only in normal B cells and are of unknown relevance in CLL B lymphocytes.