Interestingly, as opposite to what was observed in leukemia cells, HDAC and sirtuin inhibitors were poorly active and failed to show any cooperation in CD34 hematopoietic progenitors and in PBMCs. For classical HDAC inhibitors, preferential activity against malignant tissues has been reported. The fact that cancer cells frequently express higher amounts of certain HDACs, and a peculiar composition of the HDAC complexes in malignant cells have both been proposed as possible reasons for this selectivity. In contrast to Audrito and co-workers, we failed to detect increased SIRT1 expression in B-CLL cells as compared to healthy leukocytes. This could be due to the fact that these authors compared B-CLL cells to healthy B cells, while in our case SIRT1 expression in B-CLL cells was compared to its levels in PBMCs. However, as a possible explanation for the preferential activity of combined sirtuin and HDAC inhibitors in leukemias, we found that HDAC inhibition increases Bax��s levels in leukemia cells, but not in healthy leukocytes. Thus, it is likely that, by removing one arm of the two-pronged mechanism that we found underlie this form of synergy, the cooperation between the two types of agents is disabled. Further studies should address the specificity of sirtuin and HDAC inhibitors for leukemic cells. However, regardless of the underlying mechanism, these data highlight a specific requirement for sustained sirtuin and HDAC activity by leukemia cells and suggest a possible Achilles�� heel of leukemias that could be exploited therapeutically. In conclusion, sirtuin inhibitors and HDAC inhibitors cooperate in turning off cellular mechanisms that protect leukemia cells from apoptosis. Co-administration of sirtuin and HDAC inhibitors should be further examined for clinical applications. Most biological processes are NVP-BEZ235 regulated by reversible phosphorylation, and kinases play a central role in signal transmission. Kinases interconnect different signalling pathways in time and space, and confer flexibility to the regulation and coordination of multiple biological processes including cell division, GW786034 moa apoptosis and survival among others. Furthermore, alteration in kinase function is a common underlying process to many pathological situations including cancer, inflammation, and neurodegeneration. The elucidation of the human kinome has opened up new possibilities to characterize and develop strategies to manipulate these regulatory processes with therapeutic aims. Kinase domains are very suitable for development of specific inhibitors, some of which have already been applied in cancer treatment, both for tyrosine kinases, such as PDGF/kit with imatinib in a variety of tumours, or to Ser-Thr kinases such as for B-Raf in melanomas. Kinase domains in an inactive state are more structurally diverse than their activated form. However, the main problem in development of specific inhibitors resides in the high conservation of the catalytic domain, which reduces the specificity of most inhibitors by targeting several kinases simultaneously, which makes them non specific. This crossinhibition results in a significant promiscuity, which can be the cause of unexpected side effects in clinical use. The inhibition promiscuity of a kinase can be predicted based on the conservation of specific residues within the kinase fold. The VRK kinase family received its name from vaccinia virus B1R, its unique kinase required for viral replication. The VRK family has a unique ortholog in C. elegans and D. Melanogaster, but is composed of three proteins in mammals.