title: Hypoxia-inducible factors in mantle cell lymphoma: implication for an activated mTORC1→HIF-1α pathway.
abstract: Aberrant activation of phosphoinositide-3 kinase/Akt (PI3K/Akt) and mammalian target of rapamycin (mTOR) signaling is implicated in the pathogenesis of mantle cell lymphoma (MCL). We previously showed oncogenic activation of PI3K/Akt pathway in a subset of MCL patients. In this study, we investigated downstream the immunohistochemical expression of (Ser2448)pmTOR [indicative of mTOR complex 1 (mTORC1) activation status] as well as of hypoxia-inducible factor 1 alpha (HIF-1α), hypoxia-inducible factor 2 alpha (HIF-2α), p53, and p21 in the same series of MCL patients. Additionally, correlation of these proteins with activated Akt ((Ser473)pAkt) and established histological prognostic factors was examined. Thirty-five tissue samples (28 classical type and seven blastoid variant) were included. The neoplastic cells expressed (Ser2448)pmTOR in 61.7%, HIF-1α in 73.5%, HIF-2α in 23.5%, and p53 in 18.2% of patients, while p21 was negative in all examined samples. In addition, 72% of patients who expressed HIF-1α had also (Ser2448)pmTOR expression (p = 0.041). HIF-1α expression was also correlated to an elevated (≥30%) Ki-67 (p = 0.031) and blastoid variant of disease (p = 0.017). In conclusion, we report for the first time common expression of HIF-alphas, especially HIF-1α, in MCL patients. Furthermore, an overall activation of mTORC1→HIF-1α axis and a potential role of (Ser2448)pmTOR in the regulation of HIF-1α in MCL patients are suggested. Finally, HIF-1α appears to be associated with more aggressive disease. A pathogenetic role for both mTORC1 and HIF-1α in MCL is implied, which will possibly lead to more efficient target therapies.
authors.affiliation: Department of Pathology, Evangelismos General Hospital of Athens, Athens, Greece.
authors.forename: Pinelopi
authors.initials: P
authors.lastname: Argyriou
authors.forename: Sotirios G
authors.initials: SG
authors.lastname: Papageorgiou
authors.forename: Varvara
authors.initials: V
authors.lastname: Panteleon
authors.forename: Amanda
authors.initials: A
authors.lastname: Psyrri
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Bakou
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Pappa
authors.forename: Aris
authors.initials: A
authors.lastname: Spathis
authors.forename: Panagiota
authors.initials: P
authors.lastname: Economopoulou
authors.forename: Efstathios
authors.initials: E
authors.lastname: Papageorgiou
authors.forename: Theofanis
authors.initials: T
authors.lastname: Economopoulos
authors.forename: Dimitra
authors.initials: D
authors.lastname: Rontogianni
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D020522:Lymphoma, Mantle-Cell / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012694:Serine; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D012694:Serine; D058570:TOR Serine-Threonine Kinases; D000099162:Endothelial PAS Domain-Containing Protein 1; C546842:MTOR protein, human