PLX262024

GSE124102: RNA-seq data from C57BL/6N, cS5Ahi and cS5Alo CD8+ murine T-cells isolated from lymph nodes

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

Recurrent gain-of-function mutations in the transcription factor STAT5B, but not STAT5A, have been detected in mature T- and NK-cell neoplasms. No targeted therapy exists for these heterogeneous and often aggressive diseases. Also, the bystander or balancer role for STAT5A versus STAT5B is unclear. Given this and the shortage of high-fidelity models for peripheral T-cell lymphomas (PTCL), we investigated here whether graded expression of a gain-of-function STAT5A variant produces tumorous T-cell expansions. To mimic STAT5 activity we expressed a hyperactive STAT5A variant at low or high levels in the hematopoietic system of transgenic mice (termed cS5Alo and cS5Ahi). Only cS5Ahi-mice developed a lethal disease resembling human PTCL with full penetrance, characterized by massive expansion of CD8+ T-cells and by destructive organ-infiltration. Neoplastic cS5Ahi-T-cells were cytokine-hypersensitive, showed cytotoxic features, and revealed activated memory CD8+ T-lymphocyte characteristics. Histopathology analysis and mRNA expression profiles of cS5Ahi tumors revealed close correlation with distinct human PTCL subtypes, similar to the hSTAT5BN642H mouse model expressing the most frequent STAT5B mutation. We found pronounced STAT5 expression and activity in patient samples of different PTCL subsets. Clinical-grade JAK inhibitors or a selective STAT5 SH2 domain inhibitor induced cell death in murine and human PTCL cell lines and Ruxolitinib (JAK1/2) ameliorated the disease in cS5Ahi mice. SOURCE: Richard,H,Moriggl (barbara.maurer@vetmeduni.ac.at) - Unit of Functional Cancer Genomics University of Veterinary Medicine