The secret second life of an innocent chaperone: the story of CD74 and B cell/chronic lymphocytic leukemia cell survival

Abstract

This review deals with the cytokine macrophage migration inhibitory factor (MIF) and its receptor, CD74. MIF and CD74 have been shown to regulate peripheral B cell survival and were associated with tumor progression and metastasis. CD74 expression has been suggested to serve as a prognostic factor in many cancers, with higher relative expression of CD74 behaving as a marker of tumor progression. In chronic lymphocytic leukemia (CLL) cells, binding of MIF to CD74 induces nuclear factor-κB (NF-κB) activation and up-regulation of TAp63 expression, resulting in the secretion of interleukin 8 (IL-8), which in turn promotes cell survival. In addition, TAp63 expression elevates expression of the integrin VLA-4, particularly during the advanced stage of the disease. Blocking of CD74, TAp63, or VLA-4 inhibits the in vivo homing of CLL cells to the BM. Thus, CD74 and its target genes, TAp63 and VLA-4, facilitate migration of CLL cells back to the BM, where they interact with the supportive BM environment that helps rescue them from apoptosis. These results are expected to pave the way toward novel therapeutic strategies aimed at interrupting this survival pathway. One such agent, the monocolonal antibody milatuzumab directed at CD74, is already being studied in early clinical trials.