Delayed development of chronic lymphocytic leukemia in the absence of macrophage migration inhibitory factor

Survival of chronic lymphocytic leukemia (CLL) cells depends on stimuli provided by a suitable microenvironment. The factors and mechanisms providing this growth support for CLL cells are not fully understood. We found that plasma levels of macrophage migration inhibitory factor (MIF), a proinflammatory and immunoregulatory chemokine, were elevated in CLL patients. Therefore, we characterized the functional role of MIF in a CLL mouse model. For this purpose, we crossed E-TCL1 mice with MIF knockout (MIF / ) mice. The resulting TCL1 /wt MIF / mice showed a delayed onset of leukemia, reduced splenomegaly and hepatomegaly, and a longer survival than TCL1 /wt MIF wt/wt controls. Immunohistochemical examination of the lymphoid organs showed that the numbers of macrophages were significantly reduced in the spleen and bone marrow of TCL1 /wt MIF / mice compared with TCL1 /wt MIF wt/wt controls. Mechanistic studies in vitro revealed that the absence of MIF rendered CLL cells more susceptible to apoptosis. Accordingly, incubation with an anti-MIF antibody reduced the survival of CLL cells on a macrophage feeder layer. In addition, the migratory activity of TCL1 /wt MIF / macrophages was decreased compared with TCL1 /wt MIF wt/wt macrophages. Taken together, our results provide evidence that MIF supports the development of CLL by