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.