title: PTEN loss defines a PI3K/AKT pathway-dependent germinal center subtype of diffuse large B-cell lymphoma.
abstract: Diffuse large B-cell lymphoma (DLBCL) represents a heterogeneous diagnostic category with distinct molecular subtypes that can be defined by gene expression profiling. However, even within these defined subtypes, heterogeneity prevails. To further elucidate the pathogenesis of these entities, we determined the expression of the tumor suppressor phosphatase and tensin homolog (PTEN) in 248 primary DLBCL patient samples. These analyses revealed that loss of PTEN was detectable in 55% of germinal center B-cell-like (GCB) DLBCLs, whereas this abnormality was found in only 14% of non-GCB DLBCL patient samples. In GCB DLBCL, the PTEN status was inversely correlated with activation of the oncogenic PI3K/protein kinase B (AKT) pathway in both DLBCL cell lines and primary patient samples. Reexpression of PTEN induced cytotoxicity in PTEN-deficient GCB DLBCL cell line models by inhibiting PI3K/AKT signaling, indicating an addiction to this pathway in this subset of GCB DLBCLs. PI3K/AKT inhibition induced down-regulation of the transcription factor MYC. Reexpression of MYC rescued GCB DLBCL cells from PTEN-induced toxicity, identifying a regulatory mechanism of MYC expression in DLBCL. Finally, pharmacologic PI3K inhibition resulted in toxicity selectively in PTEN-deficient GCB DLBCL lines. Collectively, our results indicate that PTEN loss defines a PI3K/AKT-dependent GCB DLBCL subtype that is addicted to PI3K and MYC signaling and suggest that pharmacologic inhibition of PI3K might represent a promising therapeutic approach in these lymphomas.
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Charité Universitätsmedizin, 13353 Berlin, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Pfeifer
authors.forename: Michael
authors.initials: M
authors.lastname: Grau
authors.forename: Dido
authors.initials: D
authors.lastname: Lenze
authors.forename: Sören-Sebastian
authors.initials: SS
authors.lastname: Wenzel
authors.forename: Annette
authors.initials: A
authors.lastname: Wolf
authors.forename: Brigitte
authors.initials: B
authors.lastname: Wollert-Wulf
authors.forename: Kerstin
authors.initials: K
authors.lastname: Dietze
authors.forename: Hendrik
authors.initials: H
authors.lastname: Nogai
authors.forename: Benjamin
authors.initials: B
authors.lastname: Storek
authors.forename: Hannelore
authors.initials: H
authors.lastname: Madle
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörken
authors.forename: Martin
authors.initials: M
authors.lastname: Janz
authors.forename: Stephan
authors.initials: S
authors.lastname: Dirnhofer
authors.forename: Peter
authors.initials: P
authors.lastname: Lenz
authors.forename: Michael
authors.initials: M
authors.lastname: Hummel
authors.forename: Alexandar
authors.initials: A
authors.lastname: Tzankov
authors.forename: Georg
authors.initials: G
authors.lastname: Lenz
mesh_terms: D015331:Cohort Studies; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human