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However, its molecular mechanisms are not fully understood. In this study, we found that intracellular reactive oxygen species (ROS) are low in the SP compared to the MP. Hydrogen peroxide induces large H\u2010 and RS\u2010like cells in HL cell lines, but induces cell death in unrelated lymphoid cell lines. Microarray analyses revealed the enrichment of upregulated genes under hypoxic conditions in the SP compared to the MP, and we verified that the SP cells are hypoxic. Hypoxia inducible factor (HIF)\u20101\u03b1 was preferentially expressed in the SP. CoCl\n                    <jats:sub>2<\/jats:sub>\n                    , a HIF\u20101\u03b1 stabilizer, blunted the effect of hydrogen peroxide. Heme oxygenase\u20101 (HO\u20101), a scavenger of ROS, was triggered by HIF\u20101\u03b1. The effect of hydrogen peroxide was inhibited by HO\u20101 induction, whereas it was promoted by HO\u20101 knockdown. HO\u20101 inhibition by zinc protoporphyrin promoted the differentiation and increased ROS. These results stress the unique roles of ROS in the differentiation of HL cells. Immature HL cells are inhibited from differentiation by a reduction of ROS through the induction of HO\u20101 via HIF\u20101\u03b1. The breakdown of this might cause the accumulation of intracellular ROS, resulting in the promotion of HL cell differentiation.\n                  <\/jats:p>","DOI":"10.1111\/cas.14890","type":"journal-article","created":{"date-parts":[[2021,3,19]],"date-time":"2021-03-19T03:30:24Z","timestamp":1616124624000},"page":"2542-2555","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Differentiation of Hodgkin lymphoma cells by reactive oxygen species and regulation by heme oxygenase\u20101 through HIF\u20101\u03b1"],"prefix":"10.1111","volume":"112","author":[{"given":"Makoto","family":"Nakashima","sequence":"first","affiliation":[{"name":"Laboratory of Tumor Cell Biology Department of Computational Biology and Medical Sciences Graduate School of Frontier Sciences The University of Tokyo Tokyo 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