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 mu-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 enhancing the interaction of CLL cells with macrophages. (Blood. 2013;121(5):812-821)