Systemic and Local Adiposity in the Bone Marrow Microenvironment Associated With Improved Prognosis in Hodgkin...

Excess adiposity has been associated with Hodgkin lymphoma (HL) development, but its implications remain unclear. Bone marrow (BM), a frequent extranodal involvement site, contains both red and fatty yellow marrow. We investigated whether obesity influences HL outcomes and characterized the BM and cytokine profiles. In this retrospective study, HL patients were analyzed to assess the association between obesity with relapse and mortality. Yellow and red marrow composition were evaluated using CT imaging and correlated with HL outcomes. A nested study analyzed cytokines in the interstitial marrow fluid (IMF) and in circulation of HL patients, in comparison to a control group of healthy blood donors. Further, in vitro functional analyses were performed. Overweight/obesity in HL patients was associated with lower rates of BM involvement, disease relapse, and mortality. Moreover, dense yellow marrow was related to increased risk of death. HL subjects had elevated levels of adiponectin in IMF compared to marrow donors, whereas higher insulin, interleukin 8, and osteoprotegerin levels in IMF were associated with shorter time to relapse. At the molecular level in BM, HL patients had overexpression of LEPR and IGFBP3 in adipocytes, while stromal cells overexpressed IGF-axis receptors. In in vitro studies, human recombinant IGF-1 significantly induced the L428 HL cell line proliferation, which when combined with IGFBP-3 modified apoptosis. The current findings suggest that obesity is associated with a lower incidence of BM involvement and mortality in patients with HL. The obesity together with HL mechanistically influences systemic and local BM cytokine production, thereby impacting HL fate.