The observation that cells with greater CD44 expression achieve a more obvious survival effect indicates a dose response relationship of CD44 signaling and is consistent with enhanced tumorigenicity of cells transfected with CD44. A competing although not mutually exclusive explanation could be that U CLL cells, which usually express ZAP70, appear to have a somewhat more sensitive signal transduction Bosutinib SRC inhibitor network that contributes to tougher B cell receptor and chemokine signaling that could also contribute to enhanced CD44 signaling. To look for the mechanism involved in the anti-apoptotic effect of CD44 on CLL cells we focused on the PI3K/AKT and MAPK/ERK pathways, two important intracellular signaling pathways with prominent roles in leukemia that are involved in cell survival in response to growth factors, matrix adhesion and oncogene transformation, and that have been reported to be activated by CD44 in solid cyst and lymphoma cell lines. We found that the PI3K/AKT and MAPK/ERK pathways are activated in CLL cells following Neuroblastoma CD44 activation. Different exogenous stimuli derived from the tissue microenvironment including involvement of the T cell receptor, CD40 ligand, stroma derived element 1, whilst the pathway is constitutively active in CLL cells, and CXCL13 have already been demonstrated to promote cell survival and enhance intracellular signaling. Phosphorylation of ERK1/2 and Akt was quickly evident after CD44 stimulation and might be blocked by the PI3K inhibitor wortmannin and the MEK inhibitor, PD98059, respectively. Both inhibitors also efficiently antagonized the anti apoptotic effect of CD44 activation. We also found that stimulation of CD44 cause a rise in MCL 1 levels via a post transcriptional mechanism. This is in agreement with a recent Tipifarnib clinical trial study showing that required expression of a constitutively active mutant of Akt is sufficient to boost MCL 1 protein amounts without affecting MCL 1 mRNA transcription. ERK1/2 around the other-hand, has been proven to phosphorylate MCl 1 at Thr163, resulting in reduced MCL 1 protein degradation. MCL 1 is just a key survival factor for CLL cells and seems to be the normal survival molecule regulated by a number of different signaling pathways that include BCR excitement, CD40 ligand, BAFF, APRIL, VEGF, and stroma cell contact. In line with the activation of pathways in the micro-environment that result in improved MCL 1 proteins degrees, colleagues and Smit described greater expression of MCL 1 protein but not mRNA in CLL cells received from lymph nodes compared to cells from the peripheral blood. Increasingly, a photo is emerging that CLL cells are opportunistic cells that may use various signaling pathways to boost cell survival. Some of these pathways are tumor cell particular such as BCR signaling through a cognate antigen, while the others are more general such as cytokines and chemokine pathways.