Constitutive activation of mTOR signaling pathway in post-transplant lymphoproliferative disorders.
We examined activation of the mTOR signaling pathway in situ in the primary, normal reactive and patient-derived post-transplant lymphoproliferative disorder (PTLD) tissue samples. We accomplished this analysis by immunohistochemistry on formalin-fixed, paraffin-embedded specimens using a set of highly specific antibodies that permitted us to determine phosphorylation status of the key serines in the mTOR target proteins. Our results demonstrate that the mTOR signaling pathway is activated in reactive tissue in a highly distinct fashion with positive, typically enlarged cells being present primarily in the germinal center and, to a lesser degree, in interfollicular areas with mantle zone being conspicuously negative. We could demonstrate mTOR activation in the lesional cells in the entire spectrum of PTLD subtypes, regardless of their Epstein-Barr virus genome expression status. These data demonstrate the ubiquitous activation of the mTOR signaling pathway in PTLD and indicate that mTOR inhibitors may be effective in treatment and, notably, prevention of PTLDs given their immunosuppressive properties. Furthermore, our results define potential biomarkers of the therapeutic response. Because the constitutive mTOR activation has also been identified in cells isolated from other hematologic malignancies, the ability to examine the in vivo mTOR signaling may have implications reaching beyond the PTLD field.
El-Salem
Mouna
M
Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA.
Raghunath
Puthiyaveettil N
PN
Marzec
Michal
M
Wlodarski
Pawel
P
Tsai
Donald
D
Hsi
Eric
E
Wasik
Mariusz A
MA
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008232:Lymphoproliferative Disorders / Q000378:metabolism*; D016377:Organ Transplantation / Q000009:adverse effects*; D010750:Phosphoproteins / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D038601:Ribosomal Protein S6 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D039603:Eukaryotic Initiation Factor-4G; D010750:Phosphoproteins; D038601:Ribosomal Protein S6; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus