Rocio Renee Rubiano, BA (Advisor: Margarida Santos, PhD)

Exploring the Role of the Symmetric Dimethylarginine Writer-Reader Pair PRMT5/SND1 in JAK2-Mutant MPNs

Myeloproliferative neoplasms (MPNs) are a hematopoietic disease characterized by hyperproliferation of cells of the myeloid lineage for which current therapeutic options are limited. Discovered in 2005, the JAK2V617F mutation is the most common driver mutation in BCR-ABL negative MPNs, resulting in constitutive activation of the JAK2 protein and the JAK-STAT signaling pathway. A role for Protein Arginine Methyltransferase 5 (PRMT5) has been proposed in JAK2-mutant MPN, highlighting both a mechanism through which this mutation can drive disease progression and a potential mode of therapeutic intervention. Staphylococcal Nuclease Domain-Containing Protein 1 (SND1) is the effector molecule responsible for reading the symmetric dimethyl-arginine (SDMA) marks deposited by PRMT5, underpinning a potential role in MPN pathogenesis and treatment. SND1 is unique in its functional domains amongst eukaryotic proteins, making it a uniquely promising therapeutic target for which there is little potential for off-site effects by small molecule inhibition. Both PRMT5 and SND1 overexpression is observed in several cancers and play an oncogenic role in disease progression. Using human JAK2V617F-mutant MPN cell lines as a disease model to explore the roles of the PRMT5/SND1 axis in these diseases, we aim to establish the effects that reduced or abolished PRMT5/SND1 activity have on cell fitness by generating genetically modified cell lines and utilizing small molecule inhibitors. It is clearly demonstrated here that the reduction of PRMT5 and SND1 activity either by small molecule inhibition or genetic manipulation significantly reduces the cellular proliferation of JAK2V617F+ cell lines. Much more research is necessary to fully understand the scope of the PRMT5/SND1 axis in JAK2-mutant MPN pathogenesis. However, these findings firmly cement the importance of this axis to disease progression and the potential for therapeutic intervention.

Advisory Committee:

• Margarida Santos, PhD, Chair
• Mark Bedford, PhD
• Joya Chandra, PhD
• Xiaodong Cheng, PhD
• Deepa Sampath, PhD
• James You, MD, PhD

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