Inducible Activation of Oncogenic Syk Isoforms

The non-receptor protein tyrosine kinase Syk is a key mediator of signal transduction in B cells. By acting downstream of the B cell receptor, Syk promotes signalling pathways involved in proliferation, differentiation and in the survival of transformed B cells. The goal of this project is to analyze the mechanisms and kinetics of Syk-induced proliferation and malignant transformation. To this end, we generated a mouse model for the inducible expression of the leukemia-derived TEL-Syk fusion protein using a tamoxifen-inducible Cre mouse line for B cell-specific expression of TEL-Syk in adult mice.

Our preliminary results suggest that TEL-Syk expression leads to a marked expansion of the B cell pool in the periphery (Figure 3). Moreover, our results suggest that inducible expression of TEL-Syk in B cells is not sufficient for the transformation of B cells, as corresponding cells react with escape mechanisms leading to expression of tumor suppressors and initiation of terminal differentiation that limit the survival and expansion of the activated B cell. In a related project, we analyze the effects of expression of ITK-Syk, another leukemia-derived Syk fusion protein.