MIF loss impairs Myc-induced lymphomagenesis

Abstract

Macrophage migration inhibitory factor (MIF) is a potent regulator of inflammation and cell growth. Using the El-Myc lymphoma mouse model, we demonstrate that loss of MIF markedly delays the onset of B-cell lymphoma development in vivo. The molecular basis for this MIF-loss-induced phenotype is the perturbed DNA-binding activity of E2F factors and the concomitantly enhanced tumor suppressor activity of the p53 pathway. Accordingly, premalignant MIF-null El-Myc Bcells are predisposed to delayed S-phase progression and increased apoptosis. MIF-deficient lymphomas that do arise under these conditions contain frequent ARF deletions and p53 inactivating mutations. Conversely, MIF expression is retained in tumors developed by wild-type El-Myc animals, and the presence of one or both MIF alleles is sufficient to accelerate the development of Myc-induced lymphomas. Collectively, these results indicate that MIF promotes Mycmediated tumorigenesis, at least in the B-lymphoid compartment, and implicate MIF as a mediator of malignant cell growth in vivo.

Macrophage Migration Inhibitory Factor: a Potential Marker for Cancer Diagnosis and Therapy

“…The lipopolysaccharides induce the expression of MIF in HL-60 cells, a leukemic cell line (Nishihira et al, 1996). In mouse model, loss of MIF delayed the onset of B-cell lymphoma (Talos et al, 2005). Also even in Helicobacter pylori induced gastric cancer, MIF-TLR4 activity promotes the production of factors necessary for cancer progression (Bifulco et al, 2008;El-Omar et al, 2008).…”

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

“…MIF-deficient mice do not show developmental abnormalities and appear to have normal numbers of B cells. 6 However, they exhibit a number of immune dysfunctions when challenged by antigens or infectious agents. [19][20][21][22] Even more importantly, MIF seems to be required for bone marrow-derived dendritic cells to maintain mature B cells in the bone marrow compartment.…”

Macrophage Migration Inhibitory Factor Coordinates DNA Damage Response with the Proteasomal Control of the Cell Cycle

“…[26][27][28][29][30][31][32][33][34][35][36][37] Importantly, these initial observations were confirmed by gene knockout studies that clearly demonstrated that MIF mediates many of its growth-and tumor-promoting effects via p53-dependent mechanisms. [38][39][40] Although a number of cell cycle-associated proteins such as Rb, E2Fs, p16, p21 and p27 were also found altered in MIF deficiency, the underlying mechanism of MIF activity remained elusive at first. Subsequently, a search for intracellular MIF-binding partners by the yeast two-hybrid system yielded Jab1/CSN5 as potential candidate.…”

“…Moreover, these MIF effects were mediated by inhibiting p53 function. 38,40 Hence, MIF was classified as a tumor promoter 45 and a potential oncogene. 46 However, several other observations did not support this view: (1) While increased MIF expression in various human cancers was…”

“…44,58 In sum, our data indicate that the effects of MIF on cell survival and tumorigenesis are mediated through overlapping pathways, wherein MIF and p53 specifically antagonize each other in the cell. While the loss of MIF expression induces a p53-dependent proliferative block, 38,40 concomitant loss of p53 rescues these growth defects, but it comes at the price of increased tumorigenesis.…”