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

Abstract

IntroductionChronic lymphocytic leukemia (CLL) is a clonal B-cell disorder that is not curable by conventional chemoimmunotherapies. The leukemic transformation may be initiated by specific genomic alterations (eg, del13q) that may cause the deletion of specific micro-RNA genes (eg, miR15 and miR16) and increase the resistance of B cells toward apoptosis. 1,2 Survival of CLL cells depends on a permissive microenvironment composed of cellular components, such as macrophages, T cells, or stromal follicular dendritic cells. [3][4][5] This microenvironment provides various chemokines and angiogenic factors, which interact with leukemic cells via appropriate surface receptors and adhesion molecules. 2,5 Macrophage migration inhibitory factor (MIF) is a proinflammatory and immunoregulatory cytokine that seems to be involved in the pathogenesis of various malignant diseases. 6-9 MIF was identified as a product of T cells 10 but also other cells of the immune system (B cells, monocytes/macrophages). 11 Later, MIF was found to be an almost ubiquitous mediator secreted by a wide variety of cells in the mammalian organism, such as endothelial cells, epithelial cells, or fibroblasts. 12 Macrophages are considered to be a prime source for MIF, as they are able to secrete large amounts of MIF in response to various stimuli. 13 MIF binds to the surface receptors CD74 and CXCR2/CXCR4, thereby stimulating signaling pathways, such as MAPK, NF-B, and AKT. [14][15][16] In B cells, activation of the surface receptor complex CD74/CD44 by MIF induces the proteolytic release of the intracellular domain of CD74, which in turn initiates a signaling cascade composing Syk, AKT, and NF-B; this leads to the production of IL-8 and to an increased resistance to apoptosis via the up-regulation of BCL-2. 17,18 Thus, the MIF-MIF receptor system may be seen as a part of the B-cell costimulatory signals that are required for full B-cell activation and maturation. 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. 23 Submitted May 22, 2012; accepted October 14, 2012. Prepublished online as Blood First Edition paper, November 1, 2012; DOI 10.1182/blood-2012-05-431452.The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. MIF is overexpressed in a variety of malignancies compared with the respective primary tissues (eg, prostate, 24 colon, 25 melanoma, 26 glioblastoma, 27 breast cancer 28,29 ). This overexpression might be caused by the tumor-activated HSP90 chaperone complex that protects MIF from degradation, a...

Chronic lymphocytic leukemia nurse-like cells express hepatocyte growth factor receptor (c-MET) and indoleamine 2,3-dioxygenase and display features of immunosuppressive type 2 skewed macrophages

“…47 Interestingly, high levels of macrophage migration inhibitory factor have been detected in sera from CLL patients and lack or inhibition of this factor delays CLL development in the Eμ-TCL1 mouse model of the disease. 48 In keeping with our data, a phenotype resembling tumor-associated M2 macrophages has been recently proposed for NLC 49 as well as deregulation of genes involved in phagocytosis and inflammation for CLL-monocytes. 50 Intriguingly, acquisition of an M2 phenotype appears to be induced under the influence of malignant CLL cells as we demonstrated in normal monocytes, through IDO and c-MET upregulation.…”

Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity

“…In addition to BAG6, other factors known to compromise NK cell function were also elevated in CLL patients including macrophage migration inhibitory factor 41 (supplemental Figure 4) and soluble ligands for NKG2D (MICA/B and ULBP2) (Figure 4). This is in line with a recent study that described a prognostic relevance for soluble ULBP2 level for the therapy-free survival of CLL patients.…”

Mouse models in the study of chronic lymphocytic leukemia pathogenesis and therapy

“…86,87 Moreover, the potential role of the tumor microenvironment in signaling to malignant B cells through wingless-type MMTV integration site family (WNT) receptors 88 was addressed by genetically ablating the WNT receptor frizzled 6 (fzd6) in Em-TCL1 mice. The results suggested that dysregulated FZD6 expression modulates the disease course as it delayed but did not abrogate tumor growth.…”