Non-Toxicological Role of Aryl Hydrocarbon Receptor in Obesity-Associated Multiple Myeloma Cell Growth and Survival

SIMPLE SUMMARY: Multiple myeloma (MM) patients with obesity progress faster from myeloma precursor disorders compared to lean individuals. Understanding the biological contribution of increased adipocyte numbers in the marrow space which supports MM cell growth and survival is important for identifying novel therapeutic options to slow MM progression. We confirmed in a panel of six human MM cell lines (MM.1S, MM.1R, KMS11, H929, RPMI8226, and U266B1) that AhR activity is suppressed by exposure to secreted factors from bone marrow adipocytes. A knockdown of AhR in MM cells increased cellular growth. A computational analysis of the survival data showed that high AhR expression and low AhR target gene expression are associated with worse outcomes in MM, demonstrating that the inhibition of AhR activity supports MM cell growth and survival. ABSTRACT: Obesity is not only a risk factor for multiple myeloma (MM) incidence, but it is also associated with an increased risk of progression from myeloma precursors—monoclonal gammopathy of undetermined significance—and smoldering myeloma. Adipocytes in the bone marrow (BMAs) microenvironment have been shown to facilitate MM cell growth via secreted factors, but the nature of these secreted factors and their mechanism of action have not been fully elucidated. The elevated expression of aryl hydrocarbon receptor (AhR) is associated with a variety of different cancers, including MM; however, the role of AhR activity in obesity-associated MM cell growth and survival has not been explored. Indeed, this is of particular interest as it has been recently shown that bone marrow adipocytes are a source of endogenous AhR ligands. Using multiple in vitro models of tumor–adipocyte crosstalk to mimic the bone microenvironment, we identified a novel, non-toxicological role of the adipocyte-secreted factors in the suppression of AhR activity in MM cells. A panel of six MM cell lines were cultured in the presence of bone marrow adipocytes in (1) a direct co-culture, (2) a transwell co-culture, or (3) an adipocyte-conditioned media to interrogate the effects of the secreted factors on MM cell AhR activity. Nuclear localization and the transcriptional activity of the AhR, as measured by CYP1A1 and CYP1B1 gene induction, were suppressed by exposure to BMA-derived factors. Additionally, decreased AhR target gene expression was associated with worse clinical outcomes. The knockdown of AhR resulted in reduced CYP1B1 expression and increased cellular growth. This tumor-suppressing role of CYP1A1 and CYP1B1 was supported by patient data which demonstrated an association between reduced target gene expression and worse overall survival. These data demonstrated a novel mechanism by which bone marrow adipocytes promote MM progression.