Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma are highly dependent on oxidative phosphorylation

The metabolic properties of lymphomas derived from germinal center (GC) B cells have important implications for therapeutic strategies. In this study, we have compared metabolic features of Hodgkin-Reed-Sternberg (HRS) cells, the tumor cells of classical Hodgkin's lymphoma (cHL), one of the most frequent (post-)GC-derived B-cell lymphomas, with their normal GC B cell counterparts. We found that the ratio of oxidative to nonoxidative energy conversion was clearly shifted toward oxidative phosphorylation (OXPHOS)-linked ATP synthesis in HRS cells as compared to GC B cells. Mitochondrial mass, the expression of numerous key proteins of oxidative metabolism and markers of mitochondrial biogenesis were markedly upregulated in cHL cell lines and in primary cHL cases. NFkappaB promoted this shift to OXPHOS. Functional analysis indicated that both cell growth and viability of HRS cells depended on OXPHOS. The high rates of OXPHOS correlated with an almost complete lack of lactate production in HRS cells not observed in other GC B-cell lymphoma cell lines. Overall, we conclude that OXPHOS dominates energy conversion in HRS cells, while nonoxidative ATP production plays a subordinate role. Our results suggest that OXPHOS could be a new therapeutic target and may provide an avenue toward new treatment strategies in cHL. What's new? The surprising revelation that Hodgkin-Reed-Sternberg cells of classical Hodgkin lymphoma (cHL) originate from postgerminal center B cells raises new questions about the metabolic properties of cHL cells and possible therapeutic implications. This study shows that in contrast to the cells of other B-cell lymphomas, cHL cells require oxidative phosphorylation (OXPHOS)-dependent ATP synthesis for cell survival and cell growth, rendering them susceptible to OXPHOS inhibition. The results could inform the advance of novel therapeutic strategies in Hodgkin lymphoma.