Editors' ChoiceChronic lymphocytic leukemia

Got MIF?

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Science Translational Medicine  21 Nov 2012:
Vol. 4, Issue 161, pp. 161ec212
DOI: 10.1126/scitranslmed.3005328

Chronic lymphocytic leukemia (CLL) is a malignant disorder of B cells, but they do not work alone. In order for the cancer cells to survive and proliferate indefinitely, they require the support of stromal cells, soluble factors, and surface receptors. Immune cells such as macrophages, T cells, and stromal follicular dendritic cells also contribute to this process by secreting various chemokines, angiogenic factors, and inflammatory cytokines to create the right microenvironment. Now, macrophage migration inhibitory factor (MIF), a proinflammatory and immunoregulatory cytokine that seems to be involved in various malignancies, was found to be involved in the development of CLL as well.

Reinart et al. observed that patients with CLL had more MIF mRNA and protein in their malignant cells as compared with the B cells of healthy controls. Likewise, mice with CLL also had more MIF protein as compared with that of wild-type mice. These observations led the authors to examine the functional relevance of MIF in CLL by crossing a mouse model of CLL with MIF-deficient mice. In the resulting offspring, the absence of MIF delayed the development of overt leukemia compared with that in CLL mice that expressed MIF. The spleens and livers as well as bone marrow of both genotypes had CLL cells, but the former organs were smaller in MIF-deficient mice. MIF-deficient mice with CLL also lived longer than similar mice that had a normal amount of MIF. Further studies into how the absence of MIF could delay the onset of overt leukemia and decrease the severity of this disease showed that the absence of MIF reduced macrophage numbers, decreased the ability of these macrophages to form organized aggregates in the spleen, reduced the migratory activity of macrophages, and increased the rates of spontaneous apoptosis in CLL cells. Last, the authors showed that a neutralizing antibody to MIF was able to reduce the survival of MIF-expressing CLL cells in vitro to levels comparable with MIF-deficient CLL cells.

This study provides evidence that MIF plays an important role in the development of CLL through its effects on the survival of CLL cells and the number and migratory capacity of macrophages in leukemic homing organs. Additional studies will be needed to confirm these findings and translate them to human disease. Because the loss of MIF does not appear to be harmful, at least in mice, strategies that target MIF may provide a novel approach for treating CLL.

N. Reinart et al., Delayed development of chronic lymphocytic leukemia in the absence of macrophage migration inhibitory factor. Blood, 1 November 2012 (10.1182/blood-2012-05-431452). [PubMed]

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