title: Intracellular TCR-signaling pathway: novel markers for lymphoma diagnosis and potential therapeutic targets.
abstract: Despite the immunologic functions of T-cell receptor signaling molecules being extensively investigated, their potential as immunohistochemical markers has been poorly explored. With this background, we evaluated the expression of 5 intracellular proteins-GADS, DOK2, SKAP55, ITK, and PKCα-involved in T-cell receptor signaling in normal and neoplastic hematologic tissue samples, using antibodies raised against fixation-resistant epitopes of the 5 molecules. All 5 antibodies were associated with normal T-cell differentiation. GADS, DOK2, SKAP55, and ITK turned out to be T-cell lineage-specific markers in the setting of lymphoid and myeloid precursor neoplasms but showed differential expression in peripheral T-cell lymphoma (PTCL) subtypes, being detected in PTCL/not otherwise specified (NOS) and angioimmunoblastic T-cell lymphoma but negative in anaplastic large cell lymphoma (ALCL). Peripheral B-cell lymphomas were consistently negative for ITK, with occasional cases showing expression of DOK2 and SKAP55, and a proportion (47%) of hairy cell leukemias were GADS. Notably, PKCα highlighted a defective antigen in both PTCL/NOS (6%) and angioimmunoblastic T-cell lymphoma (10%), mostly negative in ALCL, and was aberrantly expressed in classical Hodgkin lymphoma (65%), Burkitt lymphoma (48%), and plasma cell myeloma (48%). In conclusion, all five molecules evaluated play a role in T-cell differentiation in normal and neoplastic tissues. They can be applied confidently to routine sections contributing primarily to assignment of T-lineage differentiation in the setting of hematopoietic precursor neoplasms (GADS/DOK2/SKAP55/ITK) and for the differential diagnosis between ALCL and PTCL/NOS (GADS/DOK2/SKAP55/ITK) or classical Hodgkin lymphoma (PKCα). Finally, association with specific tumor subtypes may have therapeutic potential.
authors.affiliation: *Section of Haematopathology, Department of Experimental, Diagnostic and Specialty Medicine - DIMES, University of Bologna, Italy †Department of Pathology, University College of London, London, UK ‡Department of Immunology, University of Washington, Seattle, WA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Agostinelli
authors.forename: Hasan
authors.initials: H
authors.lastname: Rizvi
authors.forename: Jennifer
authors.initials: J
authors.lastname: Paterson
authors.forename: Vishvesh
authors.initials: V
authors.lastname: Shende
authors.forename: Ayse U
authors.initials: AU
authors.lastname: Akarca
authors.forename: Elena
authors.initials: E
authors.lastname: Agostini
authors.forename: Fabio
authors.initials: F
authors.lastname: Fuligni
authors.forename: Simona
authors.initials: S
authors.lastname: Righi
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Spagnolo
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Piccaluga
authors.forename: Edward A
authors.initials: EA
authors.lastname: Clark
authors.forename: Stefano A
authors.initials: SA
authors.lastname: Pileri
authors.forename: Teresa
authors.initials: T
authors.lastname: Marafioti
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D001706:Biopsy; D002454:Cell Differentiation; D019070:Cell Lineage; D003937:Diagnosis, Differential; D005060:Europe; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008223:Lymphoma / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D010750:Phosphoproteins / Q000032:analysis; D011237:Predictive Value of Tests; D011379:Prognosis; D051571:Protein Kinase C-alpha / Q000032:analysis; D011505:Protein-Tyrosine Kinases / Q000032:analysis; D011948:Receptors, Antigen, T-Cell / Q000032:analysis*; D015398:Signal Transduction; D014861:Washington
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; C115089:DOK2 protein, human; C409587:GRAP2 protein, human; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; C108336:SKAP1 protein, human; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase; C496628:PRKCA protein, human; D051571:Protein Kinase C-alpha