title: Delayed development of chronic lymphocytic leukemia in the absence of macrophage migration inhibitory factor.
abstract: 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 Eμ-TCL1 mice with MIF knockout (MIF-/-) mice. The resulting TCL1+/wtMIF/ mice showed a delayed onset of leukemia, reduced splenomegaly and hepatomegaly, and a longer survival than TCL1+/wtMIFwt/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+/wtMIF/ mice compared with TCL1+/wtMIFwt/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+/wtMIF/ macrophages was decreased compared with TCL1+/wtMIFwt/wt macrophages. Taken together, our results provide evidence that MIF supports the development of CLL by enhancing the interaction of CLL cells with macrophages.
  
  
  CONCLUSIONS
  Targeted deletion of the gene for macrophage migration inhibitory factor (MIF) delays development of chronic lymphocytic leukemia and prolongs survival in mice. MIF recruits leukemia-associated macrophages to spleen or liver.
authors.affiliation: Department I of Internal Medicine, University Hospital Cologne, and Center for Integrated Oncology Köln-Bonn, Cologne, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Reinart
authors.forename: Phuong-Hien
authors.initials: PH
authors.lastname: Nguyen
authors.forename: Jorge
authors.initials: J
authors.lastname: Boucas
authors.forename: Natascha
authors.initials: N
authors.lastname: Rosen
authors.forename: Hans-Michael
authors.initials: HM
authors.lastname: Kvasnicka
authors.forename: Lukas
authors.initials: L
authors.lastname: Heukamp
authors.forename: Cornelia
authors.initials: C
authors.lastname: Rudolph
authors.forename: Vangica
authors.initials: V
authors.lastname: Ristovska
authors.forename: Tanja
authors.initials: T
authors.lastname: Velmans
authors.forename: Carolin
authors.initials: C
authors.lastname: Mueller
authors.forename: Katrin S
authors.initials: KS
authors.lastname: Reiners
authors.forename: Elke Pogge
authors.initials: EP
authors.lastname: von Strandmann
authors.forename: Günter
authors.initials: G
authors.lastname: Krause
authors.forename: Manuel
authors.initials: M
authors.lastname: Montesinos-Rongen
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Marco
authors.initials: M
authors.lastname: Herling
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.forename: Günter
authors.initials: G
authors.lastname: Fingerle-Rowson
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002450:Cell Communication / Q000276:immunology*; D002470:Cell Survival; D061252:Feeder Cells; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000276:immunology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human; C076231:Mif protein, mouse