The cytoplasmic kinase, zeta-associated protein of 70 kD (ZAP-70) normally expressed in T-cells and natural killer cells, is highly associated with unmutated IGHV CLL and is a surrogate marker for mutational status (Sun & Weistner 2015). ZAP-70 enhances BCR signalling providing further pro-survival, proliferation and migration messages in CLL (Zhang & Kipps 1981). ZAP-70+ CLL is associated with advanced clinical stage, higher lymphocyte counts and increased tumour proliferation. Patients with ZAP-70+ CLL have poor outcomes with reduced OS, more rapid disease progression and require treatment earlier on (Sun & Weistner 2015).
CD38 is expressed on the surface of CLL cells and is an unfavourable prognostic marker associated with shorter OS rates. Levels of CLL cells expressing CD38 that confer poor prognosis remain controversial but have been proposed to range between 7–30% (Brachtl et al., 2014). CD38 is part of a macromolecular complex including CD49d and other molecules, which, when stimulated, increases BCR signalling thus promoting cell survival, migration and homing (Zhang & Kipps 1981).
CD49d is the α4 subunit present in integrins on B- and T-cells which are involved in leukocyte development and trafficking. The integrin α4β1 specifically directs B-cells to bone marrow and germinal centres and promotes survival by up-regulation of anti-apoptotic signals, whereas the integrin α4β7 homes B-cells to the gut and lymphoid tissue (Sun & Weistner 2015). Around 40% of patients with CLL express CD49d with these patients tending to have more advanced stage disease, increased rate of disease progression and worse OS. CD49d is also associated with other unfavourable prognostic factors including ZAP-70, CD38, possibly unmutated IGHV and trisomy 12 (Sun & Weistner 2015).