Inducible expression of hyperactive Syk in B cells activates Blimp-1-dependent terminal differentiation

Oncogene. 2014 Jul 10;33(28):3730-41. doi: 10.1038/onc.2013.326. Epub 2013 Aug 19.


The non-receptor protein tyrosine kinase Syk (spleen tyrosine kinase) is an important mediator of signal transduction in B cells. By acting downstream of the B-cell antigen receptor, Syk promotes signaling pathways involved in proliferation, differentiation and survival of B cells. To study the oncogenic potential of Syk, we generated a mouse model for the inducible expression of the leukemia-derived TEL-Syk fusion protein exhibiting constitutive kinase activity. To achieve B-cell-specific expression of TEL-Syk in adult mice, we used a tamoxifen-inducible Cre mouse line. This study shows that inducible expression of TEL-Syk in B cells leads to transient proliferation and subsequent plasma cell differentiation. However, it does not lead to B-cell transformation. Instead, Syk activation induces the tumor suppressor B-lymphocyte-induced maturation protein-1 (Blimp-1), which interferes with the expression of the antiapoptotic protein Bcl-2. Combined induction of TEL-Syk with transgenic expression of Bcl-2 results in a severe phenotype and plasma cell expansion. Our results suggest that deregulated Syk activity by itself is not sufficient for the transformation of B cells, as downstream effectors, such as Blimp-1, limit the survival and expansion of the activated B cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / metabolism
  • Biomarkers / metabolism
  • Cell Differentiation*
  • Cell Survival
  • Gene Expression / drug effects
  • Integrases / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Mice
  • Mice, Transgenic
  • Mutation
  • Phenotype
  • Plasma Cells / cytology
  • Positive Regulatory Domain I-Binding Factor 1
  • Protein-Tyrosine Kinases / genetics*
  • Recombinant Fusion Proteins / genetics
  • Syk Kinase
  • Tamoxifen / pharmacology
  • Transcription Factors / metabolism*


  • Biomarkers
  • Intracellular Signaling Peptides and Proteins
  • Prdm1 protein, mouse
  • Recombinant Fusion Proteins
  • Transcription Factors
  • Tamoxifen
  • Positive Regulatory Domain I-Binding Factor 1
  • Protein-Tyrosine Kinases
  • Syk Kinase
  • Syk protein, mouse
  • Cre recombinase
  • Integrases