Alterations of Signaling Pathways in Essential Thrombocythemia with Calreticulin Mutation

PURPOSE: Though mutations of the calreticulin (CALR) gene have been identified in essential thrombocythemia patients, the detailed mechanisms for CALR mutations have not been completely clarified. Our study is aimed at characterizing alteration of protein expression in ET patients with mutated CALR(del52) and further recognizing possible involvement of signaling pathways associated with CALR mutations. PATIENTS AND METHODS: Protein pathway array was performed to analyze the expression levels of proteins involved in various signaling pathways in peripheral blood neutrophils from 18 ET patients with mutated CALR(del52), 20 ET patients with JAK2(V617F) mutation and 20 controls. RESULTS: We found 20 proteins differentially expressed in ET patients with mutated CALR(del52) compared with healthy controls. These proteins were associated with molecular mechanisms of cancer in ingenuity pathways analysis (IPA) network. We identified top ten canonical pathways which including apoptotic pathways and cellular cytokine pathways might participate in pathogenesis of ET with mutated CALR(del52). Additionally, there were 8 proteins found to be dysregulated differently between ET patients with mutated CALR(del52) and those with JAK2(V617F) mutation. These proteins might be related to the unique signaling pathways activated by CALR(del52) mutation which were different to JAK/STATs pathway by JAK2(V617F) mutation. CONCLUSION: Our study demonstrated that numerous alterations of signaling proteins and pathways in ET patients with mutated CALR(del52). These findings could help to gain insights into the pathological mechanisms of ET.