Ruxolitinib as a Novel Therapeutic Option for Poor Prognosis T-LBL Pediatric Patients

SIMPLE SUMMARY: Current treatment protocols for pediatric patients with T-Lymphoblastic lymphoma (T-LBL) allow the achievement of a complete remission in around 85% of T-LBL pediatric patients; however the overall survival rate of second-line treatments for patients with progressive disease or relapse is around 14%. Thus, the major issues to be addressed are the identification of a valuable predictor marker to foresee the disease risk and new therapeutic targets to improve relapsed/resistant patients’ outcome. We identified JAK2 Y1007-1008 as a potential prognosis marker as well as a therapeutic target for patients with progressive disease or relapse and suggest that its inhibition by ruxolitinib, a JAK1/2 FDA approved inhibitor, could represent a novel therapeutic approach to overcome therapy resistance and meliorate the outcome of pediatric T-LBL patients. ABSTRACT: Lymphoblastic lymphoma (LBL) is the second most common type of non-Hodgkin lymphoma in childhood, mainly of T cell origin (T-LBL). Although current treatment protocols allow a complete remission in 85% of cases, the second-line treatment overall survival for patients with progressive or relapsed disease is around 14%, making this the major issue to be confronted. Thus, we performed a Reverse Phase Protein Array study in a cohort of 22 T-LBL patients to find reliable disease risk marker(s) and new therapeutic targets to improve pediatric T-LBL patients’ outcome. Interestingly, we pinpointed JAK2 Y1007-1008 as a potential prognosis marker as well as a therapeutic target in poor prognosis patients. Hence, the hyperactivation of the JAK1/2-STAT6 pathway characterizes these latter patients. Moreover, we functionally demonstrated that STAT6 hyperactivation contributes to therapy resistance by binding the glucocorticoid receptor, thus inhibiting its transcriptional activity. This was further confirmed by specific STAT6 gene silencing followed by dexamethasone treatment. Finally, JAK1/2-STAT6 pathway inhibition by ruxolitinib, an FDA approved drug, in cell line models and in one T-LBL primary sample led to cell proliferation reduction and increased apoptosis. Globally, our results identify a new potential prognostic marker and suggest a novel therapeutic approach to overcome therapy resistance in pediatric T-LBL patients.