PRMT5 Promotes Progression of Chronic Lymphocytic Leukemia [ATAC-Seq]

Purpose: Richter’s Transformation (RT) is a poorly understood and often fatal progression of chronic lymphocytic leukemia (CLL) manifesting histologically as diffuse large B-cell lymphoma. PRMT5 is implicated in lymphomagenesis, but its role in CLL or RT progression is unknown. We demonstrate herein that tumors uniformly overexpress PRMT5 in patients with progression to RT. Furthermore, mice with B-specific overexpression of hPRMT5 developed a B-lymphoid expansion with increased risk of death, and Eµ-PRMT5/TCL1 double transgenic mice uniformly developed a highly aggressive disease that histologically resembles RT; where large-scale transcriptional profiling identified unique oncogenic pathways that mediate PRMT5-driven disease progression. Taken together, the discovery that PRMT5 drives oncogenic pathways promoting RT provides a compelling rationale for clinical investigation of PRMT5 inhibitors such as PRT382 in aggressive CLL/RT cases - RNA-sequencing from B cells isolated from the spleen of Eµ-PRMT5, Eµ-PRMT5/TCL1, and Eµ-TCL1 mice at ERC. - RNA-sequencing and ATAC-sequencing from B cells isolated from the spleen of Eµ-PRMT5/TCL1 and Eµ-TCL1 mice at 3 and 6 months of age. - Single cell RNA-sequencing in Eµ-PRMT5, Eµ-PRMT5/TCL1, and Eµ-TCL1 mice at ERC.