title: FOXO1 is a tumor suppressor in classical Hodgkin lymphoma.
abstract: The FOXO transcription factors control proliferation and apoptosis in different cell types. Their activity is regulated by posttranslational modifications, mainly by the PI3K-PKB pathway, which controls nuclear export and degradation. We show that FOXO1 is highly expressed in normal germinal center B cells as well as in non-Hodgkin lymphomas, including follicular lymphoma, diffuse large B-cell lymphoma, mucosa-associated lymphoid tissue non-Hodgkin lymphoma, B-cell chronic lymphocytic leukemia, and mantle cell lymphoma. In contrast, in 31 of 32 classical Hodgkin lymphoma (cHL) cases, Hodgkin and Reed-Sternberg cells were FOXO1 negative. Neoplastic cells of nodular lymphocyte-predominant Hodgkin lymphoma were negative in 14 of 20 cases. FOXO1 was down-regulated in cHL cell lines, whereas it was expressed in non-Hodgkin lymphoma cell lines at levels comparable with normal B cells. Ectopic expression of a constitutively active FOXO1 induced apoptosis in cHL cell lines and blocked proliferation, accompanied with cell-cycle arrest in the G(0)/G(1) phase. We found that, in cHL cell lines, FOXO1 is inactivated by multiple mechanisms, including constitutive activation of AKT/PKB and MAPK/ERK kinases and up-regulation of microRNAs miR-96, miR-182, and miR-183. These results suggest that FOXO1 repression contributes to cHL lymphomagenesis.
authors.affiliation: Institute of Physiological Chemistry, University of Ulm, Ulm, Germany.
authors.forename: Linka
authors.initials: L
authors.lastname: Xie
authors.forename: Alexey
authors.initials: A
authors.lastname: Ushmorov
authors.forename: Frank
authors.initials: F
authors.lastname: Leithäuser
authors.forename: Hanfeng
authors.initials: H
authors.lastname: Guan
authors.forename: Christian
authors.initials: C
authors.lastname: Steidl
authors.forename: Johanna
authors.initials: J
authors.lastname: Färbinger
authors.forename: Christin
authors.initials: C
authors.lastname: Pelzer
authors.forename: Marion J
authors.initials: MJ
authors.lastname: Vogel
authors.forename: Harald J
authors.initials: HJ
authors.lastname: Maier
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.forename: Peter
authors.initials: P
authors.lastname: Möller
authors.forename: Thomas
authors.initials: T
authors.lastname: Wirth
mesh_terms: D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor / Q000502:physiology; D056426:Genetic Loci / Q000235:genetics; D006689:Hodgkin Disease / Q000235:genetics* / Q000473:pathology; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014018:Tissue Distribution
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D035683:MicroRNAs; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases