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

ABSTRACT: 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

ORGANISM(S): Mus musculus

PROVIDER: GSE183429 | GEO | 2022/12/07

REPOSITORIES: GEO

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PRMT5 Promotes Progression of Chronic Lymphocytic Leukemia [3_vs_6_mo_RNA-Seq]

Project description: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

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Eμ-TCL1xMyc Mice as a Therapeutic Model of Accelerated B-cell Malignancy

Project description:Richter’s syndrome (RS) is an aggressive B-cell lymphoma arising from chronic lymphocytic leukemia (CLL). RS patients are generally unresponsive both to conventional and B-cell receptor-targeted agents such as ibrutinib. Mouse models that mimic the biology and therapeutic response of RS are lacking, which hampers the development of alternative treatment strategies urgently needed to improve the dismal outcome of RS patients. Aberrant Myc expression is a major factor of RS pathogenesis. To investigate Myc overexpression in the context of CLL, we generated Eµ-TCL1 mice with B-cell restricted Myc expression. Eµ-TCL1xMyc mice uniformly developed highly aggressive lymphoid disease with histologically and immunophenotypically distinct concomitant CLL and B-cell lymphoma, leading to a significantly reduced lifespan. Injection of cells from diseased Eμ-TCL1xMyc into WT mice established a disease similar to that in double-transgenic mice. Both Eμ-TCL1xMyc mice and mice with disease after adoptive transfer failed to respond to ibrutinib. Effective and durable disease control was however observed by selective inhibition of nuclear export protein exportin-1 (XPO1) using a compound currently in clinical development for relapsed/refractory malignancies, including CLL and lymphoma. Altogether, the Eµ-TCL1xMyc mouse model represents a new preclinical tool for experimental drug testing of aggressive lymphoma in the context of CLL, mimicking clinical behavior and therapeutic responses seen in RS patients.

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