Hypoxia-inducible factors in mantle cell lymphoma: implicationfor an activated mTORC1→HIF-1α pathway
- نوع فایل : کتاب
- زبان : انگلیسی
- مؤلف : Pinelopi Argyriou & Sotirios G. Papageorgiou & Varvara Panteleon & Amanda Psyrri &Vassiliki Bakou & Vassiliki Pappa & Aris Spathis & Panagiota Economo
- چاپ و سال / کشور: 2010
Description
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 Ser2448pmTOR [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 (Ser473pAkt) and established histological prognostic factors was examined. Thirty-five tissue samples (28 classical type and seven blastoid variant) were included. The neoplastic cells expressed Ser2448pmTOR 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 Ser2448pmTOR 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 Ser2448pmTOR 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.
Ann Hematol (2011) 90:315–322 DOI 10.1007/s00277-010-1070-6 Received: 27 July 2010 / Accepted: 25 August 2010 / Published online: 14 September 2010
