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

Cristina Cristofoletti, Antonella Bresin, Mario Picozza, Maria Cristina Picchio, Francesca Monzo, Mauro Helmer Citterich, Francesca Passarelli, Alessandra Frezzolini, Enrico Scala, Alessandro Monopoli, Maria Cantonetti, Roberto Benucci, Stefania D’Atri, Elisabetta Caprini, Giandomenico Russo, Maria Grazia Narducci

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Sézary 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.

Original languageEnglish
JournalLeukemia
DOIs
Publication statusAccepted/In press - Jan 1 2018

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Phosphatidylinositol 3-Kinases
Skin
70-kDa Ribosomal Protein S6 Kinases
mechanistic target of rapamycin complex 1
Chemokine CCL21
TOR Serine-Threonine Kinases
Cutaneous T-Cell Lymphoma
Metformin
Cell Communication
Up-Regulation
Therapeutics
Lymph Nodes
Cell Proliferation
Cell Line

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Blood and skin-derived Sezary cells : differences in proliferation-index, activation of PI3K/AKT/mTORC1 pathway and its prognostic relevance. / Cristofoletti, Cristina; Bresin, Antonella; Picozza, Mario; Picchio, Maria Cristina; Monzo, Francesca; Helmer Citterich, Mauro; Passarelli, Francesca; Frezzolini, Alessandra; Scala, Enrico; Monopoli, Alessandro; Cantonetti, Maria; Benucci, Roberto; D’Atri, Stefania; Caprini, Elisabetta; Russo, Giandomenico; Narducci, Maria Grazia.

In: Leukemia, 01.01.2018.

Research output: Contribution to journalArticle

Cristofoletti, Cristina ; Bresin, Antonella ; Picozza, Mario ; Picchio, Maria Cristina ; Monzo, Francesca ; Helmer Citterich, Mauro ; Passarelli, Francesca ; Frezzolini, Alessandra ; Scala, Enrico ; Monopoli, Alessandro ; Cantonetti, Maria ; Benucci, Roberto ; D’Atri, Stefania ; Caprini, Elisabetta ; Russo, Giandomenico ; Narducci, Maria Grazia. / Blood and skin-derived Sezary cells : differences in proliferation-index, activation of PI3K/AKT/mTORC1 pathway and its prognostic relevance. In: Leukemia. 2018.
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abstract = "S{\'e}zary 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.",
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AU - Cristofoletti, Cristina

AU - Bresin, Antonella

AU - Picozza, Mario

AU - Picchio, Maria Cristina

AU - Monzo, Francesca

AU - Helmer Citterich, Mauro

AU - Passarelli, Francesca

AU - Frezzolini, Alessandra

AU - Scala, Enrico

AU - Monopoli, Alessandro

AU - Cantonetti, Maria

AU - Benucci, Roberto

AU - D’Atri, Stefania

AU - Caprini, Elisabetta

AU - Russo, Giandomenico

AU - Narducci, Maria Grazia

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N2 - Sézary 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.

AB - Sézary 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.

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