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In the present study, we have identified the dihydroorotate dehydrogenase (DHODH), an essential enzyme for the\u00a0<jats:italic>de novo\u00a0<\/jats:italic>biosynthesis of pyrimidine\u2010based nucleotides, to be overexpressed in MCL in comparison to healthy peripheral blood mononuclear cells (PBMC). In vitro inhibition of the DHODH activity using a newly developed DHODH inhibitor, namely (<jats:italic>R<\/jats:italic>)\u2010HZ05, can induce MCL cell death in the nanomolar range independently than the P53 status of the investigated cell lines. Moreover, the combination of (<jats:italic>R<\/jats:italic>)\u2010HZ05 with tyrosine kinase inhibitor shows the synergistic activity on cell death. Pre\u2010clinical investigation on the efficacy of (<jats:italic>R<\/jats:italic>)\u2010HZ05 shows that it can be prolonged animal lifespan similar to ibrutinib. (<jats:italic>R<\/jats:italic>)\u2010HZ05 use in combination with tyrosine kinase inhibitor demonstrated a superior efficacy on tumor burden reduction and survival than either drug alone. We have demonstrated that the depletion of the pyrimidine nucleotide pool, using DHODH inhibitor, represents a new therapeutic strategy that may benefit MCL patients.<\/jats:p>","DOI":"10.1002\/jha2.434","type":"journal-article","created":{"date-parts":[[2022,5,16]],"date-time":"2022-05-16T03:13:21Z","timestamp":1652670801000},"page":"913-918","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Dihydroorotate dehydrogenase inhibition acts synergistically with tyrosine kinase inhibitors to induce apoptosis of mantle cell lymphoma cells"],"prefix":"10.1002","volume":"3","author":[{"given":"May","family":"Eriksen\u2010Gjerstad","sequence":"first","affiliation":[{"name":"Department of Clinical Science University of Bergen  Bergen Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ida","family":"Tveit Karlsen","sequence":"additional","affiliation":[{"name":"Department of Clinical Science University of Bergen  Bergen Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zinayida","family":"Fandalyuk","sequence":"additional","affiliation":[{"name":"Department of Clinical Science University of Bergen  Bergen Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanne","family":"Benjaminsen","sequence":"additional","affiliation":[{"name":"Department of Clinical Science University of Bergen  Bergen Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fanny","family":"Baran\u2010Marszak","sequence":"additional","affiliation":[{"name":"Inserm U978 Universit\u00e9 Paris\u201013  Bobigny France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bela","family":"Papp","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale UMR U976 Institut de Recherche Saint\u2010Louis H\u00f4pital Saint\u2010Louis, Universit\u00e9 de Paris; 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