Sezary syndrome (SS) is a rare and aggressive variant of Cutaneous T-Cell Lymphoma characterized by neoplastic distribution mainly involving blood, skin, and lymph-node. Although a role of the skin microenvironment in SS pathogenesis has long been hypothesized, its function in vivo is poorly characterized. To deepen this aspect, here we compared skin to blood-derived SS cells concurrently obtained from SS patients highlighting a greater proliferation-index and a PI3K/AKT/mTORC1 pathway activation level, particularly of mTOR protein, in skin-derived-SS cells. We proved that SDF-1 and CCL21 chemokines, both overexpressed in SS tissues, induce mTORC1 signaling activation, cell proliferation and Ki67 up-regulation in a SS-derived cell line and primary-SS cells. In a cohort of 43 SS cases, we observed recurrent copy number variations (CNV) of members belonging to this cascade, namely: loss of LKB1 (48%), PTEN (39%) and PDCD4 (35%) and gains of P70S6K (30%). These alterations represent druggable targets unraveling new therapeutic treatments as metformin here evaluated in vitro. Moreover, CNV of PTEN, PDCD4, and P70S6K, evaluated individually or in combination, are associated with reduced survival of SS patients. These data shed light on effects in vivo of skin-SS cells interaction underlying the prognostic and therapeutic relevance of mTORC1 pathway in SS.

Cristofoletti, C., Bresin, A., Picozza, M., Picchio, M.c., Monzo, F., Helmer Citterich, M., et al. (2019). Blood and skin-derived Sezary cells: differences in proliferation-index, activation of PI3K/AKT/mTORC1 pathway and its prognostic relevance. LEUKEMIA, 33(5), 1231-1242 [10.1038/s41375-018-0305-8].

Blood and skin-derived Sezary cells: differences in proliferation-index, activation of PI3K/AKT/mTORC1 pathway and its prognostic relevance

Picozza M.;Scala E.;Cantonetti M.;Russo G.;
2019-01-01

Abstract

Sezary syndrome (SS) is a rare and aggressive variant of Cutaneous T-Cell Lymphoma characterized by neoplastic distribution mainly involving blood, skin, and lymph-node. Although a role of the skin microenvironment in SS pathogenesis has long been hypothesized, its function in vivo is poorly characterized. To deepen this aspect, here we compared skin to blood-derived SS cells concurrently obtained from SS patients highlighting a greater proliferation-index and a PI3K/AKT/mTORC1 pathway activation level, particularly of mTOR protein, in skin-derived-SS cells. We proved that SDF-1 and CCL21 chemokines, both overexpressed in SS tissues, induce mTORC1 signaling activation, cell proliferation and Ki67 up-regulation in a SS-derived cell line and primary-SS cells. In a cohort of 43 SS cases, we observed recurrent copy number variations (CNV) of members belonging to this cascade, namely: loss of LKB1 (48%), PTEN (39%) and PDCD4 (35%) and gains of P70S6K (30%). These alterations represent druggable targets unraveling new therapeutic treatments as metformin here evaluated in vitro. Moreover, CNV of PTEN, PDCD4, and P70S6K, evaluated individually or in combination, are associated with reduced survival of SS patients. These data shed light on effects in vivo of skin-SS cells interaction underlying the prognostic and therapeutic relevance of mTORC1 pathway in SS.
2019
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/15 - MALATTIE DEL SANGUE
English
Biomarkers; Cell Line, Tumor; Cell Movement; Cell Proliferation; DNA Copy Number Variations; Humans; Immunohistochemistry; Immunophenotyping; Mechanistic Target of Rapamycin Complex 1; Metformin; Models, Biological; Neoplastic Cells, Circulating; Phosphatidylinositol 3-Kinases; Prognosis; Proto-Oncogene Proteins c-akt; Sezary Syndrome; Skin Neoplasms; Signal Transduction
Cristofoletti, C., Bresin, A., Picozza, M., Picchio, M.c., Monzo, F., Helmer Citterich, M., et al. (2019). Blood and skin-derived Sezary cells: differences in proliferation-index, activation of PI3K/AKT/mTORC1 pathway and its prognostic relevance. LEUKEMIA, 33(5), 1231-1242 [10.1038/s41375-018-0305-8].
Cristofoletti, C; Bresin, A; Picozza, M; Picchio, Mc; Monzo, F; Helmer Citterich, M; Passarelli, F; Frezzolini, A; Scala, E; Monopoli, A; Cantonetti, M; Benucci, R; D'Atri, S; Caprini, E; Russo, G; Narducci, Mg
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/232784
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