Survival and proliferation of CLL cells in vivo is affected by extrinsic signals which originate primarily in the microenvironment of the bone marrow and secondary lymphoid tissues. When CLL cells are removed from their natural microenvironment and cultured in vitro, they rapidly undergo apoptosis. The encouraging Crizotinib solubility interactions between the microenvironment and the neoplastic cells are complicated and multi factorial. A few of these interactions are cell cell contact dependent, while the others are mediated through chemokines, growth facets and possibly through extra-cellular matrix components. Considerable medical heterogeneity exists, and the presence or lack of somatic mutations in the immunoglobulin heavy chain variable elements of the cells divides patients in to two major prognostic sub-groups. Generally, patients with unmutated IgVH genes have a more aggressive clinical course set alongside the sub-group with mutated IgVH. ZAP70, a low receptor tyrosine kinase primarily involved with T cell receptor signal transduction, is preferentially expressed within the U CLL sub-type and confers prognostic data similar to Ig mutation status. Metastatic carcinoma CLL cells of the UCLL/ZAP70 positive subtype seem to respond better to stimulation through different pathways including the Bcell receptor and chemokine signaling than M CLL cells. The interaction between the extracellular matrix and normal or malignant cells is in part mediated through CD44. CD44 is just a type I trans membrane glycoprotein, whose main ligand is thought to be glycosaminoglycan hyaluronic acid. CD44 also can interact with numerous other extra-cellular matrix elements including osteopontin, fibronectin, laminin, and collagen. The CD44 molecule is encoded by a single gene but demonstrates substantial size heterogeneity Hedgehog inhibitor Vismodegib because of alternative splicing and post-translational modifications. The form that lacks all adjustable exons is the standard form, while CD44v symbolizes splice variants that include additional exons, giving rise to a more substantial molecule with additional extracellular domains that might change affinity to possible ligands or co receptors. The intracellular domain is shared by all CD44 isoforms. In CLL, the primary variant may be the standard CD44 form, while CD44v are merely weakly expressed in a relatively small proportion of cells. A few studies suggested that high CD44 expression can be an adverse prognostic factor related to poor clinical outcome in CLL. CD44 signaling and its downstream effects are diverse and may possibly rely on the expressed CD44 isoform, the specific ligand, the cell-type, and relationships with other transmembrane signaling components. Similarly, CD44 is an adhesion receptor that binds to extracellular matrix and regulates mobile migration, homing, and engraftment. On another hand CD44 activation may cause or protect from apoptosis.