Distinct IL-4-induced gene expression, proliferation, and intracellular signaling in germinal center B-cell-like and activated B-cell-like diffuse large-cell lymphomas.
Diffuse large B-cell lymphomas (DLBCLs) can be subclassified into germinal center B-cell (GCB)-like and activated B-cell (ABC)-like tumors characterized by long and short survival, respectively. In contrast to ABC-like DLBCL, GCB-like tumors exhibit high expression of components of the interleukin 4 (IL-4) signaling pathway and of IL-4 target genes such as BCL6 and HGAL, whose high expression independently predicts better survival. These observations suggest distinct activity of the IL-4 signaling pathway in DLBCL subtypes. Herein, we demonstrate similar IL-4 expression but qualitatively different IL-4 effects on GCB-like and ABC-like DLBCL. In GCB-like DLBCL, IL-4 induces expression of its target genes, activates signal transducers and activators of transcription 6 (STAT6) signaling, and increases cell proliferation. In contrast, in the ABC-like DLBCL, IL-4 activates AKT, decreases cell proliferation by cell cycle arrest, and does not induce gene expression due to aberrant Janus kinase (JAK)-STAT6 signaling attributed to STAT6 dephosphorylation. We found distinct expression profiles of tyrosine phosphatases in DLBCL subtypes and identified putative STAT6 tyrosine phosphatases-protein tyrosine phosphatase nonreceptor type 1 (PTPN1) and PTPN2, whose expression is significantly higher in ABC-like DLBCL. These differences in tyrosine phosphatase expression might underlie distinct expression profiles of some of the IL-4 target genes and could contribute to a different clinical outcome of patients with GCB-like and ABC-like DLBCLs.
Lu
Xiaoqing
X
Sylvester Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, University of Miami, 1475 NW 12th Ave (D8-4), Miami, FL 33136, USA.
Nechushtan
Hovav
H
Ding
Feiying
F
Rosado
Manuel F
MF
Singal
Rakesh
R
Alizadeh
Ash A
AA
Lossos
Izidore S
IS
D021581:Active Transport, Cell Nucleus; D001402:B-Lymphocytes / Q000473:pathology / Q000502:physiology*; D002455:Cell Division / Q000276:immunology; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D018858:Germinal Center / Q000473:pathology*; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics*; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000276:immunology*; D015534:Trans-Activators / Q000378:metabolism
D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D015847:Interleukin-4; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases