Prmt5 Initiates An Epigenetic Program That Promotes Progression Of Chronic Lymphocytic Leukemia

Background: Epigenetic alterations that occur as a result of arginine methyltransferase activity play a critical role in normal biological functions, and increasingly their importance has been shown in cancer initiation and progression. In particular, protein arginine methyltransferase 5 (PRMT5) is an important epigenetic regulator that influences differentiation, cell cycle progression, and many other processes. Aberrant PRMT5 activity has been implicated in tumorigenesis, however its role in the biology of chronic lymphocytic leukemia (CLL) has not been established. Despite recent improvements in therapy, CLL remains an incurable disease. While newer therapies targeting the B cell receptor pathway have shown remarkable efficacy, complete responses are not frequent. In particular, transformation of CLL to aggressive lymphoma (Richter syndrome; RS) occurs in up to 15% of patients and confers a poor prognosis; however, the mechanisms by which RS occurs are poorly understood. A better understanding of CLL progression may facilitate the development of new targeted therapies. We hypothesized that PRMT5 dysregulation initiates an epigenetic program in CLL that contributes to disease progression and potentially transformation. Moreover, we provide evidence that inhibition of PRMT5 is a promising strategy in CLL.