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Hypoxia-inducible factors in mantle cell lymphoma: implication for an activated mTORC1→HIF-1α pathway

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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 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.

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Acknowledgments

We thank Ms. Giannopoulou Ioanna, Ms. Theohari Irene, and Prof. Nakopoulou Lydia for providing us tissue samples which served as positive controls for Ser2448pmTOR staining. We also acknowledge Mr. Konstantinos Mastoris for his valuable help in designing the experiments and standardizing the antibodies.

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Authors and Affiliations

  1. Department of Pathology, Evangelismos General Hospital of Athens, Athens, Greece

    Pinelopi Argyriou, Varvara Panteleon & Dimitra Rontogianni

  2. Second Department of Internal Medicine, Propaedeutic, Hematology Unit, University of Athens, University General Hospital “Attikon”, 1 Rimini str, Haidari, 124 62, Athens, Greece

    Sotirios G. Papageorgiou, Amanda Psyrri, Vassiliki Bakou, Vassiliki Pappa, Panagiota Economopoulou, Efstathios Papageorgiou & Theofanis Economopoulos

  3. Department of Cytopathology, University General Hospital “Attikon”, Haidari, Athens, Greece

    Aris Spathis

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  1. Pinelopi Argyriou
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  2. Sotirios G. Papageorgiou
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Correspondence to Sotirios G. Papageorgiou.

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Argyriou, P., Papageorgiou, S.G., Panteleon, V. et al. Hypoxia-inducible factors in mantle cell lymphoma: implication for an activated mTORC1→HIF-1α pathway. Ann Hematol 90, 315–322 (2011). https://doi.org/10.1007/s00277-010-1070-6

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  • DOI: https://doi.org/10.1007/s00277-010-1070-6

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