Systemic anaplastic large cell lymphoma (ALCL) is the most common and the second most common T-cell lymphoma in children and adults, respectively. ALCL have an abnormal chromosome translocation t(2;5)(p23;q35), which results in a fusion gene composed of nucleophosmin (NPM) and a truncated tyrosine kinase, named anaplastic lymphoma kinase (ALK). Abnormal expression of the NPM-ALK fusion protein leads to the auto-activation of ALK. The activation of ALK has been demonstrated to be lymphomagenic both in vitro and in vivo. However, the ALK-triggered cellular signaling pathway(s) is not fully understood. Biochemical studies have shown that cellular ALK binds to several signaling molecules of the p44/42 mitogen-activated protein kinase (p44/42 MAPK) cascade. In addition, our preliminary studies demonstrated that p44/42 MAPK is highly activated in ALCL lymphoma cells and down-regulating the cellular p44/42 MAPK signaling pathway inhibits ALCL cell growth/ proliferation and induces lymphoma cell apoptosis. These findings lead us to the hypothesis that the cellular p44/42 MAPK signaling pathway plays an essential role in mediating the ALK-induced lymphomagenesis of ALCL. To confirm our hypothesis, our studies will 1) Identify the role(s) of p44/42 MAPK signaling pathway during in vitro cell transformation/ lymphomagenesis of ALCL cells using a soft agar cell colony formation assay;2) Determine the functional relationship between the p44/42 MAPK activation and abnormal NPM-ALK expression by establishing the ALCL cell models with inducible siRNA to specifically silence ALK gene in ALCL cells. Together, these studies will help us to understand the molecular mechanisms of ALCL development mediated by ALK and the p44/42 MAPK signaling pathway. More importantly, the resultant findings may lead to therapeutic advances for ALCL by identifying key signaling molecules in the lymphoma cells.
