A mix of S and [Delta]S variants of STAT3 enable survival of activated B-cell-like diffuse large B-cell lymphoma cells in culture

Activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL) is characterized by increased expression and activator of signal transducer and activator of transcription 3 (STAT3). ABC DLBCL cells require STAT3 for growth in culture. In ABC DLBCL cells, eosinophils and perhaps all cells, four variant STAT3 mRNAs (S, S, S and S) are present as a result of two alternative splicing events, one that results in the inclusion of a 55-residue C-terminal transactivation domain () or a truncated C-terminal domain with 7 unique residues () and a second that includes (S) or excludes (S) the codon for Ser-701 in the linker between the SH2 and C-terminal domains. A substantial literature indicates that both and variants are required for optimal STAT3 function, but nothing is known about functions of S variants. We used a knockdown/re-expression strategy to explore whether survival of ABC DLBCL cells requires that the four variants be in an appropriate ratio. No single variant rescued survival as well as STAT3S-C, S with activating mutations (A661C and N663C) in the SH2 domain. Better rescue was achieved when all four variants were re-expressed or S and S or S and S were re-expressed in pairs. Rescue correlated with expression of STAT3-sensitive genes NFKBIA and NFKBIZ. We consider a variety of explanations why a mix of S and S variants of STAT3 should enable survival of ABC DLBCL cells.