Blood and skin-derived Sezary cells: differences in proliferation-index, activation of PI3K/AKT/mTORC1 pathway and its prognostic relevance
2019
Sezary syndrome (SS) is a rare and aggressive variant of
Cutaneous T-Cell Lymphomacharacterized 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/
mTORC1pathway activation level, particularly of mTOR protein, in skin-derived-SS cells. We proved that SDF-1 and
CCL21chemokines, both overexpressed in SS tissues, induce
mTORC1signaling 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
druggabletargets 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
mTORC1pathway in SS.
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