In this issue of Blood, Fowler et al provide new evidence that the adipokine adiponectin may be a therapeutic target in myeloma and myeloma-associated bone disease.1
The global epidemic of obesity has been linked to several diseases such as metabolic syndrome, atherosclerosis, and several cancers including myeloma (MM).2 Several studies have now clearly shown that the accumulating fat does not simply serve as an inert storage site, but as a dynamic endocrine organ secreting hormones called adipokines.3 Adipokines play a key role in regulating energy homeostasis as well as inflammation. Adiponectin was initially identified in mid-1990s as an adipocyte-derived protein similar to complement 1q, and later shown to have anti-inflammatory properties.3,4 Several adipokines, particularly leptin and adiponectin, have also been implicated in regulating the risk of developing cancers.2 The studies by Fowler et al now add myeloma to the list of these cancers.
The initial identification of adiponectin as a potential target in myeloma was based on gene array analysis of the marrow microenvironment between KaLwRij mice that permit growth of murine 5T myeloma cells, versus nonpermissive but closely related C57Bl6 mice. Adiponectin was one of several genes in this analysis and the role of other differentially expressed genes may well be equally relevant and deserve further study. Nonetheless, increased tumor burden and MM bone disease were clearly observed in adiponectin-deficient mice and pharmacologic induction of adiponectin using an apolipoprotein peptide mimetic L-4F led to the reduction of tumor growth and prevention of MM bone disease in this model. L-4F can in principle also impact other targets, but the antimyeloma effects of L-4F seem to require adiponectin as they were lacking in adiponectin-deficient mice. These provocative findings suggest the need for further study to better understand the mechanism(s) by which host adiponectin expression might regulate MM growth. Adiponectin seems to have direct effect on both MM cells and bone cells. However, the effects of adiponectin in promoting an MM-permissive microenvironment may be multifactorial and additionally include effects on the recruitment of innate immune cells, such as macrophages.5 These elegant studies suggest a novel concept that the expression of adipokines such as adiponectin in the tumor microenvironment may regulate the permissive state of the marrow microenvironment to MM growth.
What are the potential clinical implications of this work? Detection of low adiponectin levels may suggest an increased risk for MM.6,7 While adiponectin levels are inversely related to obesity (a known risk factor for MM),8,9 the authors were careful in their use of controls matched for body mass index. Patients with monoclonal gammopathy of undetermined significance (MGUS) who progressed to MM in this small sample had lower levels of serum adiponectin compared with those that did not progress. However, this risk was restricted largely to females and the reasons behind this apparent sex bias are not readily evident at present. Nonetheless, further systematic investigation of this biomarker in ongoing prospective studies of monoclonal gammopathies may yield further insight.
The concept that the permissive state of tumor microenvironment for MM growth may be altered by adipokines such as adiponectin has important implications for preventing clinical MM. While the outlook for clinical MM has improved considerably in the past decade, the net gains in improving mortality have been much more modest compared with tumors, wherein early detection and prevention have instead been emphasized.10 The current studies set the stage for future investigations targeting obesity or pharmacologic manipulation of adipokines (such as adiponectin) as an attractive strategy for the prevention of clinical MM in selected cohorts. It is certainly now time to trim the fat.
Conflict-of-interest disclosure: The author declares no competing financial interests. ■