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Blood, 1 April 2005, Vol. 105, No. 7, pp. 2924-2932.
Prepublished online as a Blood First Edition Paper on December 9, 2004; DOI 10.1182/blood-2004-10-3820.
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NEOPLASIA
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
Xiaoqing Lu,
Hovav Nechushtan,
Feiying Ding,
Manuel F. Rosado,
Rakesh Singal,
Ash A. Alizadeh, and
Izidore S. Lossos
From the Sylvester Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, University of Miami, Miami, FL; and Department of Molecular and Cellular Pharmacology, University of Miami, Miami, FL.
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.
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