Dysregulated gene expression pathways in mice models of HR-MDS and AML post MDS mimic human disease. Mus musculus

In spite of the recent discovery of genetic mutations in most MDS, pathophysiology of those disorders remain poorly known, and few animal are available. We performed global exome specific gene expression profiling and functional pathway analysis in purified Sca1+ spleen cells of two MDS transgenic mouse models developed by our group. Those models mimic high-risk MDS (HR MDS) and AML post MDS, depending on the transgene promoters used (MRP8NRASD12/tethBCL-2 and MRP8NRASD12/MRP8hBCL-2 respectively). We found common deregulated pathways in both models showing disease continuum. The most significantly deregulated pathways identified have previously been reported in MDS patients such as cell cycle, DNA replication/damage/repair, apoptosis, immune responses and canonical Wnt pathways. Interestingly, this analysis highlights other deregulated pathways such as non-canonical Wnt pathways including Rho signaling and circadian rhythm that may be critical in a human MDS setting. Overall design: MRP8NRASD12/tethBCL-2 and MRP8[NRASD12/hBCL-2] double transgenic mice were analyzed by enriching for primitive Sca1+ cells from splenocytes. RNA was extracted analyzed for gene expression profiles using exon specific arrays.